JP2023543654A - Method for producing oxobutanol ester of polymeric carboxylic acid - Google Patents

Abstract

An object of the present invention is to produce physiologically suitable or physiologically compatible precursors and/or metabolites of 3-hydroxybutyric acid (i.e., β-hydroxybutyric acid or BHB or 3-BHB) or its salts. The objective is to provide an efficient method to do so. SOLUTION: At least one oxobutanol of the general formula (I) is combined with at least one polymeric, in particular polycondensed or polymerized, carboxylic acid (II) having at least three carboxy groups, in particular during an esterification reaction. and/or react under esterification conditions, whereby one or more oxobutanol esters of the polymeric carboxylic acid (II) can be obtained as reaction product (III). [Selection diagram] None

Description

The present invention relates to the field of keto bodies and related metabolism and the treatment of related diseases.

In particular, the present invention relates to a process for the preparation of oxobutanol esters of polymeric carboxylic acids, as well as the reaction products obtained or prepared thereby (i.e. oxobutanol esters of polymeric carboxylic acids) and their uses, in particular It relates to use in pharmaceutical compositions, such as drugs or pharmaceuticals, or in foods and/or food products, and to further applications or uses thereof.

Furthermore, the present invention relates to pharmaceutical compositions, in particular drugs or medicaments, comprising the reaction products (i.e. oxobutanol esters of polymeric carboxylic acids) obtained or produced according to the method of the present invention, and their uses or uses. .

Finally, the invention relates to foods and/or food products, in particular food supplements, functional foods, novel foods, food additives, food supplements, diet foods, power snacks, appetite suppressants, and muscle strength and/or endurance The present invention relates to sports supplements consisting of reactants (ie oxobutanol esters of polymeric carboxylic acids) obtained or produced according to the method of the invention, and to their uses or uses.

In human energy metabolism, glucose is a short-term available energy carrier and is metabolized into energy by releasing water and carbon dioxide within the mitochondria. The liver's glycogen stores are already depleted during nighttime sleep. However, the human central nervous system (CNS) and heart in particular require a continuous energy supply.

Keto bodies (synonymously called ketone bodies) are physiological substances that replace glucose and are mainly used in the central nervous system.

The term keto body specifically refers to three compounds that are formed primarily in catabolic metabolic states (eg fasting, weight loss diet, low carbohydrate diet) and can lead to ketosis. The term keto form refers in particular to acetoacetic acid (also synonymously referred to as acetoacetate) and acetone as well as 3-hydroxybutyric acid (hereinafter referred to synonymously as β-hydroxybutyric acid or BHB or 3-BHB) or Its salts (ie 3-hydroxybutyrate or β-hydroxybutyrate) are included, the latter being the most important of the three aforementioned compounds. 3-Hydroxybutyric acid or a salt thereof is physiologically known as the (R)-enantiomer, i.e. (R)-3-hydroxybutyric acid (synonymously, (3R)-3- to emphasize the chirality center at the 3-position). (also called hydroxybutyric acid) or its salts.

Physiologically, this keto body is supplied in large quantities from lipids accumulated in the body through lipolysis during fasting or starvation, and almost completely replaces glucose as an energy source.

The keto form is produced in the liver from acetyl coenzyme A (=acetyl CoA) derived from β-oxidation, and is a transportable form of acetyl coenzyme A in the human body. However, in order to utilize keto bodies, the brain and muscles must first adapt by expressing the necessary enzymes to convert keto bodies back into acetyl coenzyme A. Keto bodies contribute significantly to energy production, especially when fasting. For example, after a while, the brain can survive on only one-third of the daily amount of glucose.

Physiologically, the keto form is synthesized from two molecules of activated acetic acid in the form of acetyl coenzyme A, a common intermediate product of fatty acid breakdown, and further synthesizes an acetyl coenzyme A unit and the enzyme HMG-CoA-synthase. The intermediate product 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is produced using HMG-CoA lylase, which then cleaves acetoacetate. These three steps take place only in the mitochondria of the liver (linen cycle), and 3-hydroxybutyrate is ultimately produced in the cytoplasm by D-β-hydroxybutyrate dehydrogenase. Furthermore, HMG-CoA is the final product of the decomposition of the amino acid leucine, and acetoacetate is produced during the decomposition of the amino acids phenylalanine and tyrosine.

Natural decarboxylation converts acetoacetate to acetone, which can be detected in the breath of people with diabetes or on a diet. It is no longer used by the body. However, the proportion of acetone contained in keto bodies is small.

Thus, acetoacetate is reductively converted to the physiologically relevant form of 3-hydroxybutyric acid or 3-hydroxybutyrate, but can also decompose to physiologically unusable acetone with the release of carbon dioxide. It can be detected and sniffed in urine and exhaled breath in severe ketosis, ketoacidosis (eg, patients with type 1 diabetes who are not supplemented with insulin).

3-Hydroxybutyric acid is currently used and sold in the weight training field as the sodium, magnesium and calcium salts.

However, since plants do not produce 3-hydroxybutyric acid and 3-hydroxybutyric acid in animal organisms occurs only in the carcasses of lean animals in ketosis, 3-hydroxybutyric acid causes nausea when administered orally. Furthermore, 3-hydroxybutyric acid is unknown or, from an evolutionary point of view, known only in very small amounts in humans. 3-Hydroxybutyric acid, in its free acid and salt forms, also has a very bitter taste and causes severe vomiting and nausea.

Moreover, the salts of 3-hydroxybutyric acid are not tolerated in large amounts by patients, especially neonates, but even adults, since these compounds have a kidney-damaging effect.

In addition, the plasma half-life of 3-hydroxybutyric acid and its salts is extremely short, and ketosis only lasts about 3 to 4 hours even after ingesting several grams. cannot be said to be continuously effective. Metabolic diseases can lead to life-threatening conditions.

Therefore, for the treatment of such metabolic diseases, currently so-called medium-chain triglycerides, so-called MCTs, are used for ketogenic therapy, i.e. caproic, caprylic and capric acids (i.e. saturated The metabolic conversion of linear C ₆ -, C ₈ - and C ₁₀ -fatty acids) is contemplated.

But basically, from a pharmaceutical and clinical point of view, 3-hydroxybutyric acid is a more effective pharmaceutical and pharmacological target molecule, and according to the prior art, it can be used in principle for the treatment of numerous diseases. However, it cannot be used because it is not physiologically compatible (for example, diseases related to disorders of energy metabolism, especially keto metabolism, or neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, fat metabolic diseases, etc.).

The table below indicates, purely by way of example and in no way limiting, potential treatment options or possible indications for the active ingredient 3-hydroxybutyric acid.

Therefore, it is important from a pharmaceutical and clinical point of view to be able to find effective precursors or metabolites that are physiologically accessible to 3-hydroxybutyric acid or its salts, directly or indirectly, especially in the physiological metabolism of the human body or animals. desirable.

Consequently, the prior art is not lacking in attempts to find physiologically suitable precursors or metabolites of 3-hydroxybutyric acid or its salts. However, so far no efficient compounds have been found in the prior art. Furthermore, access to such compounds is not possible or easily possible according to the prior art.

The problem underlying the present invention is therefore to provide physiologically suitable or physiologically compatible precursors and/or metabolites of 3-hydroxybutyric acid (i.e. β-hydroxybutyric acid or BHB or 3-BHB) or salts thereof. To provide an efficient method for manufacturing.

It is particularly desirable that such a method makes it possible to utilize the respective BHB precursor and/or BHB metabolite efficiently, especially in large quantities, and without generating large amounts of toxic by-products.

In a completely surprising manner, the applicant has demonstrated that oxobutanol esters of polymeric carboxylic acids are efficient and physiologically effective or physiologically compatible precursors and/or metabolizers of the keto form 3-hydroxybutyric acid or its salts. and, in this connection, an efficient method for producing these compounds which allows access to these compounds directly and effectively, in particular economically and industrially viable. discovered or developed.

Therefore, in order to solve the above problem, the present invention proposes - according to a first aspect of the invention - a process for the preparation of oxobutanol esters of polymeric carboxylic acids according to claim 1; Particularly special and/or advantageous embodiments of the inventive method are the subject of the associated dependent claims.

Furthermore, the invention - according to a second aspect of the invention - provides a reaction product obtainable according to the process according to the invention according to the independent claim (claim 33) or according to the respective claims (claims 34 to 46). Furthermore, the present invention relates to oxobutanol esters of polymeric carboxylic acids or to mixtures of at least two oxobutanol esters of polymeric carboxylic acids obtainable in this respect according to the respective claim (claim 47); Particularly particular and/or advantageous embodiments of this aspect of are the subject of the associated dependent claims.

The invention likewise relates - according to a third aspect of the invention - to a pharmaceutical composition, in particular a drug or medicament, according to the respective independent claim (claim 48); and/or advantageous embodiments are the subject matter of the relevant dependent claims.

Furthermore, the invention provides - according to a fourth aspect of the invention - for the prophylactic and/or therapeutic treatment of diseases of the human or animal body according to the respective independent claim (claim 50) or for use therein. or an inventive oxobutanol ester or an inventive mixture of at least two polymeric carboxylic acids.

Furthermore, the invention provides - according to a fifth aspect of the invention - according to the associated independent claim (claim 51) for the prophylactic and/or therapeutic treatment of diseases of the human or animal body; It relates to the use of an inventive reaction product or an oxobutanol ester of a polymeric carboxylic acid according to the invention or an inventive mixture of at least two polymeric carboxylic acids for the production of a medicament.

Furthermore, the invention - according to a sixth aspect of the invention - provides inventive reaction products of polymeric carboxylic acids or oxobutanol esters of the invention or polymeric carboxylic acids according to the associated independent claim (claim 52). It concerns the use of the inventive mixture of at least two oxobutanol esters of molecular carboxylic acids.

Furthermore, the invention - according to a seventh aspect of the invention - relates to a food product and/or food product according to the associated independent claim (claim 53), and furthermore relates to a food product and/or food product according to the invention. Particularly special and/or advantageous embodiments of are the subject of the associated dependent claims.

Finally, the invention provides that - according to an eighth aspect of the invention - the reaction products or polymeric carboxylic acids of the invention in foods and/or food products according to the associated independent claim (claim 55) Furthermore, particularly special and/or advantageous embodiments of the use according to the invention relate to the use Subject matter of dependent claims.

The following features, embodiments, advantages, etc., which are hereinafter described only with respect to one aspect of the invention to avoid repetition, naturally apply to other aspects of the invention as appropriate, and there is no need to mention them separately. Needless to say.

Furthermore, individual aspects and embodiments of the invention are also considered to be disclosed in any combination with other aspects and embodiments of the invention, in particular resulting from a backward reference in any claims. It goes without saying that any combination of features and embodiments is also considered to be broadly disclosed with respect to all possible combinations resulting therefrom.

With respect to all relative or percentage weight-based data, in particular relative amount or weight data, provided below, within the scope of the present invention, these refer, in particular, to all ingredients or components, as defined below. It should further be noted that the amount containing 100% by weight or always adding to 100% by weight, respectively, should be chosen by the person skilled in the art; however, this is obvious to the person skilled in the art.

Further, those skilled in the art can set specifications within the following range as needed without departing from the scope of the present invention.

Furthermore, it applies that all values or parameters etc. specified below can be determined or specified, in principle, by standardized or explicitly specified measurement methods, or by determination or measurement methods well known to those skilled in the art. .

Having said this, the present invention will now be explained in more detail:

According to a first aspect of the invention, the subject of the invention is therefore oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)- A method for producing 2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, comprising:
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl The general formula (I) is
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is reacted with at least one polymer having at least 3 carboxy groups, in particular with a polycondensed or polymerized carboxylic acid (II), in particular in an esterification reaction and/or or react under esterification conditions,
This provides, as reaction product (III), one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2- Butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester can be obtained.

Accordingly, the present invention provides a method for producing oxobutanol esters of polymeric carboxylic acids, particularly 3-hydroxybutanoic acid esters. Note that 3-hydroxybutanoic acid ester is sometimes referred to synonymously as 3-hydroxybutyric acid ester or 4-oxo-2-butanol.

The term "polymeric carboxylic acid" as used herein refers to a polymer based on carboxylic acid (ie, a polymer formed by polycondensation or polymerization of carboxylic acid). Polymeric carboxylic acids should not be confused with polycarboxylic acids, which are molecules with two or more carboxy groups. In particular, the polymeric carboxylic acid has at least two repeat units derived from or based on a monomeric carboxylic acid. In this context, "derived from" means that the repeat unit is formed from a monomeric carboxylic acid, in particular by (poly)condensation (e.g. esterification) with a further identical monomeric carboxylic acid; i.e. It means that the repeating unit is, for example, a corresponding monomeric carboxylic acid radical (dicarboxylic acid radical), especially one that has been esterified twice.

Strictly speaking, in the context of the present invention, oxobutanol of general formula (I) (in particular referred to as 3-hydroxybutyric acid ester) is a (C ₁ -C ₅ -alkyl)-3-hydroxybutanoic acid ester (=3 -hydroxybutyric acid (C ₁ -C ₅ -alkyl) ester), i.e. the C ₁ -C ₅ -alkyl ester of 3-hydroxybutyric acid, which is synonymously 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol, or (hydroxy-C ₃ -C ₅ -alkyl)-3-hydroxybutanoic acid ester (=3-hydroxybutyric acid (hydroxy-C ₃ -C ₅ -alkyl) ester) , namely the hydroxy-C ₃ -C ₅ -alkyl ester of 3-hydroxybutyric acid, which synonymously refers to 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol. It's one of those things.

In this regard, 3-hydroxybutanoic acid esters can be prepared by esterifying free 3-hydroxybutyric acid with the corresponding alcohol (eg monoalcohol or diol). Below, the synthesis of hydroxybutyl 3-hydroxybutanoate (ie 3-hydroxybutanoic acid of general formula (I) where R ¹ = droxybutyl) is shown schematically.

Furthermore, the synthesis of hydroxypentyl 3-hydroxybutanoate (ie 3-hydroxybutanoic acid of general formula (I) where R ¹ =hydroxypentyl) is shown schematically below.

The preparation or synthesis of further 3-hydroxybutanoic acid esters is carried out analogously.

In the process according to the invention, the starting material or the compound oxobutanol or the 3-hydroxybutanoic ester of general formula (I) acts as an esterifying alcohol via the hydroxy group, in which the carboxylic acid of the polymeric carboxylic acid (II) The corresponding oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-C ₁ -C ₅ -alkoxy)-2-butanol esters or polymeric carboxylic acids, can be obtained as reaction products (III) by reacting with the groups. The 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of acid (II) is formed.

In the present invention, the polymeric carboxylic acid (II) used and the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid (II) are both organic carboxylic acids (i.e., one or more carboxy groups (-COOH)). is an organic compound with acidic properties).

The use of polymeric carboxylic acids can provide molecules with high drug densities, particularly 3-hydroxybutanoic acid ester or 3-BHB or corresponding derivative densities.

Also, if desired, the product (ie, oxobutanol ester of a polymeric carboxylic acid) can be provided in solid form by using appropriate reactants and adjusting reaction conditions. Solid dosage forms are advantageous for use in or as drugs, pharmaceuticals, or foods and/or food products. Additionally, oxobutanol esters of polymeric carboxylic acids, compared to the corresponding oxobutanol esters of monomeric carboxylic acids, exhibit different solubility, which can be influenced by the choice of reactants and reaction conditions. It is something.

Surprisingly, the Applicant has provided 3-hydroxybutyric acid or its derivatives (i.e. esters) in an organically compatible form, while at the same time making the 3-hydroxybutyric acid or its esters easily accessible as such, especially by the animal or human body. We have found a way to release the

Furthermore, the applicant has decided to provide an organoleptic compatible form of 3-hydroxybutyric acid such that there is a delayed effect, i.e. the 3-hydroxybutyric acid is released continuously over a longer period of time. Successful.

Other degradation or cleavage products (ie, cleavage products released in addition to 3-hydroxybutyric acid) may also be available or at least processed within the body. In particular, in addition to 3-BHB, decomposition products are reactants, products, or intermediates of the citric acid cycle, or derivatives or salts formed by oxidation of reactants, products, or intermediates of the citric acid cycle. and cleavage products are released.
Further degradation and cleavage products formed during the release of 3-hydroxybutyric acid can therefore be utilized by the animal or human body as an energy source.

By using a polymeric carboxylic acid, since there are many free carboxy groups, multiple oxobutanols or 3-hydroxybutanoic acid esters can react with the polymeric carboxylic acid (i.e., multiple oxobutanols or 3-hydroxybutanoic acid esters can react with the polymeric carboxylic acid). (acid ester is added to a polymeric carboxylic acid), a high density of 3-BHB or its ester is present in one molecule, resulting in a high drug density.

As mentioned above, the applicant has quite surprisingly discovered that the oxobutanol esters of polymeric carboxylic acids prepared thereby, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy )-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is a physiologically compatible precursor and/or metabolizer of 3-hydroxybutyric acid or its salts. It has been discovered that the product is efficient because it is physiologically compatible and can also be used in larger quantities in pharmaceutical or clinical applications.

The above-mentioned oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or polymeric carboxylic acids, which can be efficiently accessed for the first time by the production method according to the present invention The 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of the acid is a physiologically and pharmaceutically relevant alternative to free 3-hydroxybutyric acid or its salts or esters. It shows something.

Oxobutanol esters of polymeric carboxylic acids by conventional organic synthesis, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ The production of -alkoxy)-2-butanol esters is complex and costly due to the increased tendency of 3-hydroxybutyric acid to polymerize and other undesirable side reactions (eg dehydration, decomposition, etc.). Within the scope of the invention, oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-( It has now been possible for the first time to provide an efficiently working production process in which hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters can be produced without undesirable side effects, especially in one step or in a one-pot synthesis.

The process of the present invention therefore comprises the preparation of non-toxic oxobutanol esters of polymeric carboxylic acids, in particular 4-oxobutanol esters of polymeric carboxylic acids, from known, commercially available, in particular physiologically harmless components or reactants (starting compounds). -4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester as part of an uncomplicated production process. This is the first time that it has been possible to provide this service as a service. The obtained oxobutanol ester of polymeric carboxylic acid, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C _{3 )} of polymeric carboxylic acid -C ₅ -alkoxy)-2-butanol ester is physiologically degraded, particularly in the stomach and/or intestine, and releases or generates the target molecule "3-hydroxybutyric acid" or its salt or ester as an active ingredient or active ingredient. It is possible to do so.

Further, the above-mentioned oxobutanol ester of the polymeric carboxylic acid, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy- The C ₃ -C ₅ -alkoxy)-2-butanol esters can also have an acceptable taste, so that they can be tolerated even when administered orally in large amounts over long periods of time (e.g., daily doses of 50 g or more). .

Similarly, the process according to the invention provides for the production of oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters of polymeric carboxylic acids, which are free from toxic impurities. ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester.

Furthermore, using suitable starting materials, the method can also be carried out enantioselectively. For example, according to the invention, the manufacturing method provides a biologically relevant form, i.e. the (R)-enantiomer of 3-BHB, for example, in a manner that does not burden the renal system of a patient when administered orally. (ie excretion via the kidneys), by enzyme catalysis or by targeted selection of the starting compounds (reactants) used. However, it is also possible in principle to enrich the (S)-enantiomer of 3-BHB under certain useful conditions.

Furthermore, the production method according to the invention, including any further processing or purification steps, can be operated economically and can also be carried out on a large scale.

In particular, since the production method of the present invention uses commercially available starting compounds or starting materials, large-scale synthesis is easy and feasible, and even when carried out on a large scale, it is relatively simple overall. Enabling process control.

In contrast to conventional prior art manufacturing methods, the manufacturing method according to the invention does not use complex starting materials and in particular only one step. Nevertheless, excellent yields are achieved according to the invention and the formation of by-products is minimized or avoided.

Furthermore, the method of the invention is simple and economical. In particular, the process according to the invention is usually carried out in the absence of a solvent and/or solvent-free (ie as a reaction in mass or as a reaction in matter or as a so-called bulk reaction). As a result, the reaction product obtained is not contaminated with solvent and there is no need to remove the solvent and discard or recycle it in a costly and energy-intensive manner after carrying out the process or reaction. Furthermore, no harmful by-products are formed.

The production process according to the invention comprises different oxobutanol esters of polymeric carboxylic acids, in particular different 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters of polymeric carboxylic acids or different 4-oxo- Mixtures consisting of 4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters, so-called oxobutanol esters consisting of at least two, especially three, of polymeric carboxylic acids, in particular at least two of polymeric carboxylic acids. , especially from three 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters This produces a mixture of The resulting raw reaction product or raw mixture is purified by known methods, in particular by removing remaining starting compounds and/or by-products present, and - optionally - by known methods, in particular by distillation and/or chromatography (e.g. fractionation of polymeric carboxylic acids into individual oxobutanol esters, i.e. separation of the respective monoesters, diesters, etc. or concentrated fractions of the individual esters, etc.). and fractionation into fractions with diluted parts).

As mentioned above, according to a first aspect of the invention, the invention provides oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy) esters of polymeric carboxylic acids. -2-Butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester.
wherein the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl. General formula (I) preferably representing ethyl
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4- (Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is
reacting with at least one polymer having at least three carboxy groups, in particular polycondensed or polymerized carboxylic acids (II), in particular in an esterification reaction and/or under esterification conditions;
Thereby, as reaction product (III) one or more oxobutanol esters of polymeric carboxylic acids (II), in particular oxobutanol esters of polymeric carboxylic acids, in particular one or more 4-oxobutanol esters of polymeric carboxylic acids, -4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained.

According to a particular embodiment of the invention, the compounds of general formula (I) can be used in racemic form or in the form of the (R)-enantiomer. The (R)-configuration refers to the asymmetric carbon atom at the 3-position of the compound of general formula (I).

According to the invention, preference is given to the case in which the radical R ¹ in general formula (I) represents ethyl.

Thus, according to the invention, 3-hydroxybutanoic acid ethyl ester of the formula CH ₃ -CH(OH)-CH ₂ -C(O)OC ₂ H ₅ (synonymously , 3-hydroxybutyric acid ethyl ester or 4-ethoxy-4-oxo-2-butanol) is preferably used.

This allows particularly efficient process control and high yields with minimized or suppressed by-product formation. Furthermore, 3-hydroxybutanoic acid ethyl ester or 4-ethoxy-4-oxo-2-butanol are also commercially available in large quantities, in particular as starting compounds, for example by Claisen condensation of ethyl acetate.

According to a particular embodiment of the invention, the polymeric carboxylic acid (II) is in the form of a free carboxylic acid, in the form of a (partial) salt of a polymeric carboxylic acid, or in the form of a (partial) salt of a polymeric carboxylic acid. ) can be used in the form of esters, especially in the form of free polymeric carboxylic acids.

In connection with the present invention, it is provided that the polymeric carboxylic acids (II) are prepared by polycondensation or by polymerization, in particular by ring-opening polymerization.

In production by polycondensation, for example, a polymeric carboxylic acid is esterified by an esterification reaction between a carboxy group of one carboxylic acid and a carboxy group of another carboxylic acid. In this context, the same carboxylic acids are esterified with each other, ie two molecules of the same carboxylic acid, for example two molecules of tartaric acid or two molecules of citric acid, are esterified with each other. The reaction method is schematically shown below using tartaric acid as an example:

Alternatively, polymeric carboxylic acids can be prepared by ring-opening polymerization of lactones of carboxylic acids. A lactone is a heterocyclic compound having an ester bond within the ring. The reaction method will be schematically shown below using tartaric acid as an example.

The corresponding reactants for the production of polymeric carboxylic acids (ie, monomeric carboxylic acids or their corresponding lactones) are commercially available, and polycondensation or ring-opening polymerizations are simple and can be carried out on a large scale. Alternatively, many polymeric carboxylic acids are commercially available. The corresponding reactants (i.e., monomeric carboxylic acids or their corresponding lactones) for the production of commercial polymeric carboxylic acids are commercially available, and polycondensation or ring-opening polymerization is straightforward. , can be implemented on a large scale. Alternatively, many polymeric carboxylic acids are also commercially available.

For the method according to the invention, it is preferred if the polymeric carboxylic acid (II) is an ingredient, in particular an additive, approved under food law.

Ingredients and additives approved under food law are listed on the food additive list throughout the EU, and are given a unique label (so-called E number). For example, metatartaric acid (E353), also synonymously called polytartaric acid, is a polymeric carboxylic acid approved under the Food Law.

Furthermore, it is also preferable that the polymeric carboxylic acid (II) has two terminals and/or a primary carboxy group. In this regard, the terminal and/or primary carboxy groups are located at opposite ends of the molecule.

According to a preferred embodiment of the process according to the invention, the polymeric carboxylic acid (II) has at least 2, in particular 2 to 20, derived from monomeric carboxylic acids on which the polymeric carboxylic acid (II) is based. Preferably it is provided that it contains 2 to 10, more preferably 3 to 7 repeat units.

The monomeric carboxylic acid that forms the basis of the polymeric carboxylic acid (II) is a carboxylic acid that has been polycondensed or polymerized to synthesize the corresponding polymeric carboxylic acid (II). For example, tartaric acid is the lower monomeric carboxylic acid in polymeric tartaric acid (metartaric acid), and in the case of polycitric acid, citric acid is the lower monomeric carboxylic acid.

In particular, the repeating units each contain at least one free carboxy group. Due to the presence of at least one free carboxy group in the repeating unit, particularly large amounts of oxobutanol can be esterified to polymeric carboxylic acids, providing a high active ingredient density.

Typically, the monomeric carboxylic acids underlying the repeating units and/or polymeric carboxylic acids (II) are derived from and/or selected from hydroxydi- and polycarboxylic acids, preferably tartaric acid, malic acid, from and/or selected from the group consisting of acids and citric acids and combinations and mixtures thereof.

The term "derived from" herein refers to hydroxy acids and polycarboxylic acids whose lower layers are repeating units and monomeric carboxylic acids, respectively. In the case of repeating units, this is formed by esterification of hydroxydi- and polycarboxylic acids, and it is not the hydroxydi- and polycarboxylic acids themselves but their (di)carboxylic esters that form the repeating units. Hydroxy di- and polycarboxylic acids refer to organic substances having at least one hydroxyl group and at least two carboxy groups.

These carboxylic acids are particularly suitable for conversion into polymeric carboxylic acids and are additives or ingredients that are commercially available and furthermore approved for use in foods.

Usually, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid (II) is a naturally occurring carboxylic acid produced in human and/or animal metabolism or a derivative thereof, particularly a reaction product thereof.

Polymeric carboxylic acids based on carboxylic acids or derivatives that are part of human and/or animal metabolism and are reactants or products or intermediates of human and/or animal metabolism can be used as pharmaceuticals, pharmaceuticals or foods. and/or particularly suitable for use in food products. It is particularly advantageous in this regard if the monomeric carboxylic acid on which the polymeric carboxylic acid or its derivative is based is one that originates in, originates from, or is associated with the citric acid cycle. It is. In this context, derivatives represent, for example, salts or esters obtained by oxidation of metabolites (eg from the citric acid cycle). using polymeric carboxylic acids based on monomeric carboxylic acids or derivatives that are part of human and/or animal metabolism and are reactants or products or intermediates of human and/or animal metabolism; , an additional energy source (in addition to the ketogenic 3-hydroxybutyric acid or 3-hydroxybutanoic acid ester) is provided, which can be adapted to the human and/or animal body when using the reaction product according to the invention. It is possible.

In particular, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid (II) is an ingredient, especially an additive, approved by the Food Law.

For example, the following carboxylic acids are listed in the list of food additives and are also suitable for the preparation of polymeric carboxylic acids (II) that can be used in the process according to the invention: tartaric acid (E334), citric acid (E330) and malic acid (E296). These acids are part of the citric acid cycle or can be obtained by oxidation of metabolites of the citric acid cycle. The citric acid cycle is a cycle of biochemical reactions that plays an important role in the metabolism of aerobic cells in living organisms, and is mainly used for the oxidative decomposition of organic substances for the purpose of energy production and provision of biosynthetic intermediates. It is something. Thus, when using the reaction product (III) obtained from the process according to the invention, the carboxylic acid produced by the decomposition is one that can be utilized by the body as a further alternative energy source.

According to a particular embodiment of the process of the invention, the polymeric carboxylic acids (II) are selected from polymeric hydroxydi- and polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polyphosphoric acid and polycitric acid and (partial) salts and (partial) esters and combinations and mixtures thereof, more preferably polytartaric acid (metartaric acid or E353) and (partial) salts and (partial) esters and mixtures thereof, even more preferred Preferably it is selected from the group of tartaric acid (metartaric acid or E353).

Polytartaric acid or its salt here is also referred to as polytartrate, polyphosphoric acid or its salt is also referred to as polyphosphate, and polycitric acid or its salt is also referred to as polycitrate.

According to a particular embodiment of the invention, the polymeric carboxylic acid (II) is polytartaric acid (metartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, in particular polytartaric acid ( Metatartaric acid or E353) is preferred.

Polytartaric acid, also synonymously called metatartaric acid, is an additive (E number: E353) approved under the Food Act and is therefore particularly suitable for the production of products for use as medicines, medicines or foods and/or food products. Are suitable.

According to a particular embodiment of the invention, the polymeric carboxylic acid (II) has the general formula (IIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIa)
It corresponds to
Here, in general formula (IIa),
- X is an organic radical, saturated or unsaturated, linear, having 3 to 10, preferably 3 to 8 carbon atoms and having 1 to 3 carboxy groups and optionally at least one hydroxy group; or a branched organic radical;
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ and Y ² are saturated or unsaturated straight chains having terminal and/or primary carboxy groups and having 3 to 7 carbon atoms and 4 to 8 oxygen atoms, each independently of the other. Or it represents a branched organic radical.

According to a particular embodiment of the invention, the polymeric carboxylic acid (II) has the general formula (IIb)
Y ¹ -[O-cH(COOH)-CHZ-C(O)] ⁿ -Y ² (IIb)
It is preferable to correspond to
Here, in general formula (IIa),
・Z represents hydrogen or a hydroxy group;
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents the group HOOC-CH(OH)-CH when Z is a hydroxy group Showing (OH)-C(O)-;
・Y ² represents the group -O-CH(COOH)-CH ₂ -COOH when Z is hydrogen, and represents the group -O-CH(COOH)-CH(OH ) - to indicate COOH.

According to another particular embodiment of the invention, the polymeric carboxylic acid (II) has the general formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
It is preferable to correspond to
Here, in general formula (IIc),
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH(OH)-C(O)-,
・Y ² represents a group -O-CH(COOH)-CH(OH)-COOH.

に対応することが好ましい。
ここで、一般式（ＩＩｄ）において、変数ｎは、２以上の（整数）数、特に２～２０の範囲内、好ましくは２～１０の範囲内、より好ましくは３～７の範囲内の整数を示すものである。 According to a particular embodiment of the invention, the polymeric carboxylic acid (II) has the general formula (IId)

It is preferable to correspond to
Here, in the general formula (IId), the variable n is an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7. This shows that.

According to a particular embodiment of the invention, the present invention provides oxobutanol esters of polymeric carboxylic acids, particularly 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy- _C3 - _C5 -alkoxy)-2-butanol ester, in particular a process as described above. .
wherein the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, or General formula (I) preferably representing ethyl
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
selected from polymeric hydroxydi- and -polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polyphosphoric acid and polycitric acid, as well as (partial) salts and (partial) esters thereof and combinations and mixtures thereof , more preferably selected from the group of polytartaric acid (metartaric acid or E353) and their (partial) salts and (partial) esters and combinations and mixtures, even more preferably selected from polytartaric acid (metartaric acid or E353) in particular in an esterification reaction and/or under esterification conditions,
Thereby, one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -C ₅ -) of the polymeric carboxylic acid (II), are used as reaction products. Alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is what is obtained.

According to another particular embodiment of the invention, the invention according to this aspect of the invention provides oxobutanol esters of polymeric carboxylic acids, particularly 4-oxo-4-(C ₁ -C _{5 )} of polymeric carboxylic acids. -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters, in particular the processes described above.
wherein the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, or General formula (I) preferably representing ethyl
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
at least one carboxylic acid (II) selected from polytartaric acid (metatartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, in particular polytartaric acid (metatartaric acid or E353); , in particular in an esterification reaction and/or under esterification conditions,
This provides, as reaction product (III), one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -) of the polymeric carboxylic acid (II). C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained.

According to yet another particular embodiment of the invention, the invention according to this aspect of the invention provides oxobutanol esters of polymeric carboxylic acids, particularly 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy- _C3 - _C5 -alkoxy)-2-butanol ester, in particular the method described above,
wherein the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably General formula (I) represents ethyl
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH(OH)-C(O)-,
・^Y2 represents the group -O-CH(COOH)-CH(OH)-COOH General formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
in an ester reaction and/or in esterification conditions, with at least one carboxylic acid (II) of
Thereby, as reaction product (III), one or more oxobutanol esters of polymeric carboxylic acid (II), in particular one or more 4- Oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained.

の少なくとも１つのカルボン酸（ＩＩ）と、エステル反応において及び／又はエステル化条件において、反応し、
これによって、反応生成物（ＩＩＩ）として、反応生成物（ＩＩＩ）として、高分子カルボン酸（ＩＩ）の１つ以上のオキソブタノールエステル、特に高分子カルボン酸（ＩＩ）の１つ以上の４－オキソ－４－（Ｃ_１－Ｃ_５－アルコキシ）－２－ブタノールエステル又は４－オキソ－４－（ヒドロキシ－Ｃ_３－Ｃ_５－アルキコシ）－２－ブタノールエステルが得られるものである。 Moreover, according to certain embodiments according to this aspect of the invention, the invention also provides oxobutanol esters of polymeric carboxylic acids, particularly 4-oxo-4-(C ₁ -C ₅ - alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters, in particular as described above. .
wherein the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably General formula (I) where represents ethyl
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
- The variable n represents an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7. )

in an ester reaction and/or in esterification conditions, with at least one carboxylic acid (II) of
Thereby, as reaction product (III), one or more oxobutanol esters of polymeric carboxylic acid (II), in particular one or more 4- Oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained.

According to a particular embodiment of the invention, said reaction is carried out in the absence and/or solvent-free. This means that it is carried out as a reaction in mass, as a reaction in matter, as a so-called bulk reaction. This has the advantage that the reaction products obtained are not contaminated with solvents and do not have to be removed and disposed of or recycled in a costly and energy-intensive manner after carrying out the process or reaction. . Surprisingly, this process or reaction nevertheless proceeds with high conversions and yields, at least essentially without the formation of significant by-products.

According to another particular embodiment of the invention, the reaction may be carried out in the absence and/or without a catalyst; otherwise the reaction may alternatively be carried out with a catalyst, in particular an enzyme and/or a catalyst. Alternatively, it may be carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst, where the catalyst is recycled after the reaction.

In the process according to the invention, it is particularly preferred if the reaction is carried out in the absence and/or without a solvent and if the reaction is carried out in the absence and/or without a catalyst.

Since neither a solvent nor a catalyst is used, the reaction products are not contaminated by solvents that are not completely removed or catalysts that are not completely removed. Additionally, energy-intensive and costly removal and separation steps are eliminated. Surprisingly, the inventive process according to this preferred embodiment is nevertheless economical and results in high conversions without significant by-product formation.

As mentioned above, according to certain embodiments of the manufacturing method of the invention, the reaction can be carried out in the absence of and/or without a catalyst.

Provided that the reaction is carried out in the absence and/or without a catalyst, the reaction is carried out in the range from 20°C to 160°C, in particular in the range from 50°C to 150°C, preferably in the range from 70°C to 140°C. It is more preferable to conduct the reaction at a temperature within the range of 80°C to 135°C, and even more preferably within the range of 100°C to 130°C.

In the case of the reaction in the absence of a catalyst, the applied pressure range can be varied within wide limits. In particular, the reaction is carried out in the absence of a catalyst and/or without a catalyst, in the range from 0.0001 bar to 10 bar, in particular in the range from 0.001 bar to 5 bar, preferably from 0.01 bar to 2 bar. , more preferably at a pressure in the range from 0.05 bar to 1 bar, even more preferably at a pressure of about 1 bar.

If the reaction is carried out in the absence of a catalyst, the reaction is preferably carried out in the presence of an inert gas, in particular helium, argon, nitrogen, preferably nitrogen. In particular, undesired side reactions, especially those due to oxidation or hydrolysis, are prevented in this way.

However, alternative to this particular embodiment, it is also possible, for example, for the reaction to be carried out in the presence of an enzyme as catalyst.

In this regard, the enzymes are especially selected from synthetases (ligases), catalases, esterases, lipases and combinations thereof. According to the invention, a synthetase (synonym ligase) is an enzyme, in particular of the class of ligases, which are enzymes that catalyze the joining of two or more molecules by covalent bonds. In the present invention, catalase refers to an enzyme having the ability to convert hydrogen peroxide into oxygen and water. The term esterase refers in particular to enzymes that have the ability to hydrolyze (saponify) esters into alcohols and acids; these are therefore especially hydrolases; lipolytic esterases are also called lipases. Lipases in the sense of the present invention are enzymes that have the ability to break down free fatty acids from lipids, such as in particular glycerides (lipolysis).

In this regard, the enzymes used as catalysts are Candida antarctica, Mucor miehei (Rhisomucor miehei), Thermomyces lanuginosa, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens. , Rhizopus deremar and Pseudomonas species and combinations thereof, preferably Candida antarctica, Mucor miehei (Rhizomucor miehei) and Thermomyces lanuginosa.

According to a particular embodiment, said enzyme is immobilized in immobilized form, in particular on a carrier, preferentially a polymeric carrier, preferably a hydrophobic polymeric organic carrier, more preferably a poly(meth)acrylic resin based carrier. and can be used.

In the present invention, when an enzyme is used as a catalyst, it is preferable to recycle the enzyme after the reaction.

If the reaction is carried out within the framework of the inventive production process in the presence of an enzyme as catalyst, said reaction is carried out in the range from 10°C to 80°C, in particular in the range from 20°C to 80°C, preferably from 25°C to It is preferable to conduct the reaction at a temperature within the range of 75°C, more preferably within the range of 45°C to 75°C, even more preferably within the range of 50°C to 70°C.

When using enzymes as catalysts, the amount of enzyme used can be varied within wide limits. In particular, the enzyme is present in an amount in the range from 0.001% to 20% by weight, in particular in the range from 0.01% to 15% by weight, based on the total amount of starting compounds (I) and (II). It can be used within the range of 0.1% to 15% by weight, preferably within the range of 0.5% to 10% by weight. Nevertheless, deviations from the above amounts may be made in each case or for the particular application without departing from the scope of the invention.

According to a particular embodiment of the invention, when the reaction is carried out in the presence of an enzyme as a catalyst, the range of applied pressure can also be varied within a wide range. Typically, the reaction in the presence of an enzyme is carried out at a pressure within the range 0.0001 bar to 10 bar, especially within the range 0.001 bar to 5 bar, preferably within the range 0.01 bar to 2 bar, more preferably 0.05 bar. It can be carried out at pressures in the range ˜1 bar, more preferably around 0.5 bar.

According to a particular embodiment of the invention, wherein said reaction is carried out in the presence of an enzyme as catalyst, said reaction is carried out in the presence of an enzyme, preferably in the presence of an inert gas, in particular helium, argon or nitrogen. Preferably, the reaction is carried out in the presence of nitrogen. As mentioned above in connection with the reaction in the absence of a catalyst, undesired side reactions, in particular those due to oxidation or hydrolysis, can be prevented by reaction in the presence of an inert gas.

According to another alternative embodiment of the invention, the reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst, for example.

According to this alternative embodiment of the invention, wherein said reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst, said catalyst is in particular (i) a basic catalyst, in particular an alkali or alkaline earth hydroxides and alkali or alkaline earth alcohol salts, such as NaOH, KOH, LiOH, Ca(OH) ₂ , NaOMe, KOMe and Na (OBu-tert.), (ii) acidic catalysts, especially mineral acids, and organic acids such as sulfuric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, paratoluenesulfonic acid and carboxylic acids, (iii) Lewis acids, especially Lewis acids based on titanium, tin, zinc and aluminum compounds. , for example titanium tetrabutyrate, stannic acid, zinc acetate, aluminum trichloride, aluminum triisopropyl, and (iv) heterogeneous catalysts, especially those based on mineral silicates, germanates, carbonates and aluminum oxides. , for example selected from zeolites, montmorillonites, mordenites, hydrotalcites and aluminas and combinations thereof.

In this embodiment, Lewis acids based on titanium, tin, zinc, aluminum compounds, such as titanium tetrabutyrate, stannic acid, zinc acetate, aluminum trichloride, aluminum triisopropyl, are preferably used as catalysts.

In particular, according to this embodiment it is also preferred if the metal-containing and/or metal-based acidic or basic catalyst is recycled after the reaction.

According to a particular embodiment of the invention, when said reaction is carried out in the presence of metal-containing and/or metal-based, acidic or basic catalysts, it is possible to vary the temperature within a wide range. . In particular, the reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst at a temperature in the range from 20°C to 160°C, especially in the range from 50°C to 150°C, preferably from 70°C to 140°C. The temperature range is preferably 80°C to 135°C, and even more preferably 100°C to 130°C.

Furthermore, according to this embodiment, the catalyst (ie, in the presence of metal-containing and/or metal-based, acidic or basic catalysts) can be varied within wide quantitative ranges. The catalyst is therefore preferably present in an amount of from 0.01% to 30% by weight, in particular from 0.05% to 15% by weight, based on the total amount of starting compounds (I) and (II). is used in an amount ranging from 0.1% to 15% by weight, preferably from 0.2% to 10% by weight. However, for the specific application and each case, it is possible to depart from the above amounts without departing from the scope of the invention.

According to this particular embodiment of the invention, if said reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst, the pressure range varies within a wide range as well. Is possible. In particular, the reaction is carried out in the range from 0.0001 bar to 10 bar, especially in the range from 0.001 bar to 5 bar, preferably in the range from 0.01 bar to 2 bar, more preferably from 0.05 bar to It is carried out at a pressure in the range of 1 bar, more preferably at a pressure of about 1 bar, in the presence of a metal-containing and/or metal-based, acidic or basic catalyst.

Furthermore, according to this particular embodiment of the invention, said reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst, while said reaction is carried out in the presence of an inert gas, In particular, it is carried out in the presence of helium, argon or nitrogen, preferably in the presence of nitrogen. As mentioned above, by performing the reaction in the presence of an inert gas, undesirable side reactions, particularly due to oxidation and hydrolysis, can be prevented.

As regards the total amount of starting materials or starting compounds, they can vary within wide limits.

Considering the economics of the process and the optimization of the course of the process, in particular with regard to the minimization of by-products, the oxobutanol of the general formula (I) based on the carboxy group of the polymeric carboxylic acid (II) can be used in equimolar amounts. to a molar excess of 200 mol%, in particular in a molar amount ranging from an equimolar amount to a molar excess of 150 mol%, preferably in a range from an equimolar amount to a molar excess of 100 mol%. It is advantageous if

Similarly, taking into account the economics of the process and the optimization of the course of the process, in particular the minimization of by-products, the oxobutanol of general formula (I) and the polymeric carboxylic acid (II) may be mixed in a ratio of 1:1 to 10:1. oxobutanol/polymeric carboxylic acid (II) moles of general formula (I) within the range of 2:1 to 8:1, preferably 3:1 to 6:1. Advantageously, it is used in a ratio.

In the process according to the invention, water is simultaneously formed during the reaction of the oxobutanol of the general formula (I) with the polymeric carboxylic acid (II) in the free acid form. It is particularly preferred that water is recovered from the reaction, especially continuously, preferably by continuous distillation or adsorption removal.

Alternatively, in the process according to the invention, during the reaction of the oxobutanol of general formula (I) with the polymeric carboxylic acid (II) in the form of an ester, 1 mol of the corresponding alcohol is added for each mole of reacted ester groups. It is formed. In particular, it is preferred that the alcohol is recovered from the reaction, in particular continuously, particularly preferably by continuous distillation or adsorption removal.

In this context, the term "reacted ester group" means an ester group that is transesterified in the process according to the invention, ie an ester group that reacts with oxobutanol. In this regard, the corresponding alcohol is separated. That is, when an ethyl ester of a polymeric carboxylic acid is present, ethanol is resolved by transesterification with oxobutanol.

Continuous removal of by-products (water, alcohol, etc.) particularly shifts the chemical equilibrium towards the products and increases the conversion.

In the production process according to the invention, the composition of the reaction product, in particular the presence of various oxobutanol esters of polymeric carboxylic acids and their proportions in the case of mixtures, depends on the reaction conditions, in particular on the reaction temperature (conversion temperature). and/or by selecting the reaction pressure (conversion pressure); and/or by providing no catalyst or a catalyst and by selecting the catalyst with respect to type and/or amount; Alternatively, it can be controlled and/or regulated by selecting the amount of starting compounds (educts) and/or by providing for the removal of optionally formed by-products, in particular water and/or alcohol. .

Therefore, the exact composition can be adjusted depending on the application, in particular by adjusting the number of substituted oxobutanol radicals (3-hydroxybutanoic acid ester radicals), for example, oxobutanol or 3-hydroxybutanol per molecule. The density of keto bodies in the form of hydroxybutanoic acid esters can be intentionally adjusted.

After the reaction, the reaction product obtained can be subjected to further purification or work-up steps.

In this case, the obtained reaction product can be fractionated after the reaction, particularly by distillation.

It is also preferred that unreacted starting compounds (I) and/or (II) be separated from the reaction product and then recycled.

According to a special embodiment of the production process according to the invention, the hydroxy and/or carboxy groups still present in the reaction product after said reaction has been carried out are at least partially, preferably completely, functionalized. It is particularly possible to proceed in such a way that it is esterified, in particular esterified.

In particular, said reaction is followed by a partial, especially complete, functionalization, especially esterification, of the hydroxy and/or carboxy groups still present.

In this particular embodiment of the process of the invention, the functionalization, in particular esterification, of the hydroxy and/or carboxy groups still present _is carried out, for example with C ₂ -C ₃₀ -carboxylic acids or with C 2 -C 30 -carboxylic acids in the case of free hydroxy groups. This can be carried out by reaction of -C ₃₀ -fatty acids, in the case of free carboxy groups, of C ₂ -C ₃₀ -fatty alcohols with carboxylic acid anhydrides. These are linear or branched, saturated or mono- or polyunsaturated C ₂ -C ₃₀ -carboxylic acid anhydrides or C ₂ -C ₃₀ -fatty acid anhydrides or C ₂ -C ₃₀ -aliphatic alcohols. It may be. In this connection, the hydroxyl groups still present can be reacted, in particular with carboxylic anhydrides or fatty acids, and the carboxyl groups still present can be reacted, in particular with fatty alcohols, to give the respective corresponding esters.

In the process according to the invention, reaction product (III) is one or more oxobutanol esters of polymeric carboxylic acids (II), in particular one or more 4-oxo-4-( Preferably, C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters are obtained.

In the production process according to the invention, as reaction product (III) one or more oxobutanol esters of polymeric carboxylic acids (II) as defined above, in particular one or more of polymeric carboxylic acids (II) It is preferred that 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of .

In the production process according to the invention, at least two, in particular at least three different oxobutanol esters of polymeric carboxylic acids (II) as defined above are used as reaction products (III), in particular at least three different oxobutanol esters of polymeric carboxylic acids (II) as defined above. ) of one or more 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters of Preferably, a mixture is obtained.

A further subject of the invention is, according to a second aspect of the invention, a reaction product, in particular a (chemical) product or product mixture, of a polymeric carboxylic acid, preferably obtainable by the method defined above. Oxobutanol esters, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2 of polymeric carboxylic acids - butanol esters or mixtures of oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo esters of polymeric carboxylic acids It is a mixture of -4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol.

In particular, the invention also relates to oxobutanol esters of polymeric carboxylic acids as defined above or below, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters of polymeric carboxylic acids. ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester.

According to a particular embodiment of this aspect of the invention, at least one carboxy group, in particular at least one terminal and/or primary carboxy group, of the polymeric carboxylic acid is an oxobutanol, in particular of the general formula (I).
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one 3-hydroxybutanoic acid, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C ₃ -C ₅ -Alkoxy)-2-butanol is preferred.
Here, in the general formula (I), the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, It represents hydroxybutyl or hydroxypentyl, more preferably ethyl.

According to another particular embodiment of this aspect of the invention, said polymeric carboxylic acid is produced by polycondensation or by polymerization, especially ring-opening polymerization.

According to this aspect of the invention, it is preferred if the polymeric carboxylic acid is a food law approved ingredient, especially an additive. As already mentioned in connection with the process according to the invention, the oxobutanol esters of the invention containing polymeric carboxylic acids approved under food law are particularly suitable for use in or as medicines, drugs, foods and/or food products. suitable.

Furthermore, according to this aspect of the invention, it is preferred if the polymeric carboxylic acid consists of two terminal and/or primary carboxy groups.

According to a particular embodiment of this aspect of the invention, said polymeric carboxylic acid has at least 2, in particular 2 to 20, preferably 2 It is advantageous if it contains ˜10 repeating units, more preferably 3 to 7 repeating units.

Typically, each of the repeating units contains at least one free carboxy group. If each repeating unit contains at least one free carboxy group, it is possible to provide high drug concentrations since each free carboxy group can be esterified with or with oxobutanol.

In particular, the repeat units and/or the monomeric carboxylic acids on which the polymeric carboxylic acids are based are derived from and/or selected from hydroxydi- and polycarboxylic acids, preferably tartaric acid, malic acid and citric acid as well as these. Derived from and/or selected from the group of combinations and mixtures, more preferably derived from and/or selected from tartaric acid.

As mentioned above, "derived from" means that the hydroxy di- and polycarboxylic acids form repeating units or monomeric carboxylic acid groups, respectively. In the case of repeating units, this is formed by esterification of hydroxydi- and polycarboxylic acids, and it is not the hydroxydi- and polycarboxylic acids themselves that form the repeating units. Hydroxy di- and polycarboxylic acids refer to organic substances having at least one hydroxy group and at least two carboxy groups.

Preferably, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid is a naturally occurring carboxylic acid or its derivative produced in human and/or animal metabolism, especially a reaction product, especially a carboxylic acid or its derivative, especially a reaction product. It is a product.

As mentioned above, when the reaction product obtained is used in or as a drug, medicine, food and/or food product, human and/or Alternatively, polymeric carboxylic acids based on carboxylic acids or derivatives that are part of animal metabolism are particularly compatible. It is particularly advantageous in this regard if the monomeric carboxylic acid on which the polymeric carboxylic acid or its derivative is based is one that occurs in, originates from, or is associated with the citric acid cycle. be. In this context, derivatives can represent, for example, salts or esters obtained by oxidation of metabolites (eg from the citric acid cycle). using polymeric carboxylic acids based on monomeric carboxylic acids or derivatives that are part of human and/or animal metabolism or are reactants or products or intermediates of human and/or animal metabolism; This makes it possible to supply or make available an additional energy source (in addition to the ketogenic 3-hydroxybutanoic acid or 3-hydroxybutanoic acid) to the human and/or animal body when using the reaction product according to the invention. can.

In particular, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid is preferably an ingredient, especially an additive, approved by the Food Law.

As mentioned above, for example, the following carboxylic acids are included in the list of food additives and are also suitable for the production of polymeric carboxylic acids (II) that can be used in the process according to the invention: tartaric acid (E334), Citric acid (E330) and malic acid (E296). These acids are either part of the citric acid cycle or obtained by oxidation of metabolites of the citric acid cycle. The citric acid cycle is a cycle of biochemical reactions that plays an important role in the metabolism of aerobic cells in living organisms, and mainly involves the oxidative decomposition of organic substances for the purpose of supplying intermediate products for energy production and biosynthesis. It is something. The acid produced by decomposition when using the reaction product (III) obtained from the process according to the invention can therefore be utilized in the body as another alternative energy source.

According to a particular embodiment of this aspect of the invention, said polymeric carboxylic acids are selected from the group of polymeric hydroxydi- and polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polymeric acids and polycitric acid. and (partial) salts and (partial) esters thereof and combinations and mixtures thereof, more preferably from polytartaric acid (metartaric acid or E353) and (partial) salts and (partial) esters thereof and mixtures thereof. , and even more preferably polytartaric acid (metartaric acid or E353).

According to a preferred embodiment of this aspect of the invention, said polymeric carboxylic acid is selected from polytartaric acid (metartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, in particular polytartaric acid. (metatartaric acid or E353).

According to another particular embodiment of aspects of the invention, the polymeric carboxylic acid has the general formula (IIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIa)
This corresponds to
Here, in general formula (IIa),
- X is an organic radical, in particular a saturated or unsaturated linear radical containing 3 to 10, preferably 3 to 8 carbon atoms and containing 1 to 3 carboxy groups and optionally at least one hydroxy group; or indicating a branched organic radical;
- the variable n indicates an (integer) number greater than or equal to 2, in particular an integer in the range of 2 to 20, preferably an integer in the range of 2 to 10, more preferably an integer in the range of 3 to 7;
・Y ¹ and Y ² are saturated or unsaturated linear chains having terminal and/or primary carboxy groups and having 3 to 7 carbon atoms and 4 to 8 oxygen atoms, respectively Or showing a branched organic radical.

According to yet another particular embodiment of aspects of the invention, the polymeric carboxylic acid has the general formula (IIb)
Y ¹ -[O-CH(COOH)-CHZ-C(O)] _n -Y ² (IIb)
This corresponds to
Here, in general formula (IIb),
・Z represents hydrogen or hydroxy group;
- The variable n represents an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents the group HOOC-CH(OH)-CH(OH) when Z is a hydroxy group -C(O)-;
・Y ² represents a group -O-CH(COOH)-CH ₂ -COOH when Z is hydrogen, and represents a group -O-CH(COOH)-CH(OH)- when Z is a hydroxy group Show COOH.

According to yet another particular embodiment of this aspect of the invention, the polymeric carboxylic acid has the general formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
This corresponds to
Here, in general formula (IIc),
- The variable n represents an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents a group HOOC-CH(OH)-CH(OH)-C(O)-;
・Y ² represents a group -O-CH(COOH)-CH(OH)-COOH.

に対応するものである。
ここで、一般式（ＩＩｄ）において、
・変数ｎは、２以上の（整数）数を示し、特に２～２０の範囲内、好ましくは２～１０の範囲内、より好ましくは３～７の範囲内の整数を示すこと。 Further, according to certain embodiments of this aspect of the invention, the polymeric carboxylic acid has the general formula (IId)

This corresponds to
Here, in general formula (IId),
- The variable n represents an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7.

It is also an object of the invention according to certain embodiments to obtain oxobutanol esters of polymeric carboxylic acids, in particular as defined above, 4-oxo-4-(C ₁ -C ₅ -alkoxy)- The object of the present invention is to provide 2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester.
Here, the oxobutanol ester has the general formula (IIIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIIa)
This corresponds to
Here, in general formula (IIIa),
- X is an organic radical, in particular a saturated ^or It denotes an unsaturated, straight-chain or branched organic radical, where the radical R ³ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C( O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably Ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ and Y ² are each independently saturated or ^unsaturated , linear or It represents a branched organic radical, where in the group -COOR ⁴ , the radical R ⁴ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl thing;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above, preferably as a (further) condition that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above.

A further object of the invention according to certain embodiments is also oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy) of polymeric carboxylic acids as defined herein. -2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester,
Here, the oxobutanol ester is
General formula (IIIb)
Y ¹ -[O-CH(COOR ³ )-CHZ-C(O)] _n -Y ² (IIIb)
It corresponds to
Here, in general formula (IIIb),
・Z represents hydrogen or hydroxy group;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ represents a group R ⁴ OOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents a group R ⁴ OOC-CH(OH) when Z is a hydroxy group -CH(OH)-C(O)-, where the radical R ⁴ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents , C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, more preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl ;
・Y ² represents a group -O-CH(COOR ⁴ )-CH ₂ -COOR ⁴ when Z is hydrogen, and represents a group -O-CH(COOR ⁴ )- when Z is a hydroxy group. CH(OH)-COOR ⁴ , where the radical R ⁴ independently of each other represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl thing;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above; A further) condition is that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above.

Another object of the invention according to a further particular embodiment is also the oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -) of polymeric carboxylic acids as defined above. alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester,
The oxobutanol ester has the general formula (IIIc)
Y ¹ -[O-CH(COOR ³ )-CH(OH)-C(O)] _n -Y ² (IIIc)
It corresponds to
Here, in the general formula (IIIc),
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
・Y ¹ represents the group R ⁴ OOC-CH(OH)-CH(OH)-C(O)-, where the radical R ⁴ is hydrogen or the radical -CH(CH ₃ )-CH ₂ -C( O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, more preferably ethyl , hydroxybutyl or hydroxypentyl, more preferably ethyl:
・Y ² represents the group -O-CH(COOR ⁴ )-CH(OH)-COOR ⁴ , where the radical R ⁴ is independently of each other hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably represents ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above; A further) condition is that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above.

に対応するものであり、
ここで、一般式（ＩＩＩｄ）において、
・変数ｎは、２以上の（整数）数、特に２～２０範囲内、好ましくは２～１０の範囲内、より好ましくは３～７の範囲内の整数を示すこと；
・Ｒ^３は、それぞれの繰り返し単位に関して互いに独立した水素又はラジカル－ＣＨ（ＣＨ_３）－ＣＨ_２－Ｃ（Ｏ）ＯＲ^１を示し、ここでラジカルＲ^１はＣ_１－Ｃ_５－アルキル又はヒドロキシ－Ｃ_３－Ｃ_５－アルキル、特にエチル、ブチル、ペンチル、ヒドロキシブチル又はヒドロキシペンチル、好ましくはエチル、ヒドロキシブチル又はヒドロキシペンチル、より好ましくはエチルを示すこと；
・Ｒ^４は、互いに独立した、水素又はラジカル－ＣＨ（ＣＨ_３）－ＣＨ_２－Ｃ（Ｏ）ＯＲ^１を示し、ここでラジカルＲ^１は、Ｃ_１－Ｃ_５－アルキル又はヒドロキシ－Ｃ_３－Ｃ_５－アルキル、特にエチル、ブチル、ペンチル、ヒドロキシブチル又はヒドロキシペンチル、好ましくはエチル、ヒドロキシブチル又はヒドロキシペンチル、より好ましくはエチルを示すこと；
ただし、ラジカルＲ^３及びＲ^４の少なくとも１つ、特に少なくとも２つが、上記に定義されるようなラジカル－ＣＨ（ＣＨ_３）－ＣＨ_２－Ｃ（Ｏ）ＯＲ^１を示すことを条件とし、好ましくは（さらなる）条件として、少なくとも１つのラジカルＲ^４が、上記に定義されるようなラジカル－ＣＨ（ＣＨ_３）－ＣＨ_２－Ｃ（Ｏ）ＯＲ^１を示すこと。 Furthermore, it is an object of the invention according to yet another particular embodiment to obtain oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -) of polymeric carboxylic acids as defined above. It is also to provide an alkoxy)-2-butanol ester or a 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester,
The oxobutanol ester has the general formula (IIId)

It corresponds to
Here, in the general formula (IIId),
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
・R ⁴ represents, independently of each other, hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above, preferably as a (further) condition that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above.

An object of the invention according to a particular embodiment is furthermore a mixture of at least two, in particular at least three, different oxobutanol esters of polymeric carboxylic acids, in particular one or more oxobutanol esters of polymeric carboxylic acids as defined above. -oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or a mixture of 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester.

Reaction products of the invention, respectively obtained by the process of the invention or as defined above, and/or oxobutanol esters of polymeric carboxylic acids, in particular obtained by the process of the invention 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of a polymeric carboxylic acid, or , inventive oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C 1 -C 5 -alkoxy)-2-butanol esters or 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters of polymeric carboxylic acids as defined above. -4-(Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or the mixture obtained by the production process of the invention or the mixture of the invention as defined above are respectively conventional It has a number of advantages and special configurations compared to the technology.

The applicant has surprisingly found that the reaction products obtained by the process of the invention or the reaction products of the invention as defined above, respectively, and/or oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy) of polymeric carboxylic acids as defined above -2-butanol ester and/or the mixture obtained by the production process of the invention or the mixture of the invention as defined above, on the one hand, physiologically, in particular in the gastrointestinal tract, 3-hydroxybutanol or As a precursor or metabolite of 3-hydroxybutyric acid or its salts, since it is converted into its salts and on the other hand constitutes at the same time good physiological compatibility or tolerability, especially with respect to non-toxicity and acceptable organic food properties. It was found to be suitable.

Reaction products of the invention obtained by the process of the invention or as defined above, respectively, and/or oxobutanol esters of polymeric carboxylic acids, in particular polymers as defined above. 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of carboxylic acid, and/or , the mixture obtained by the production process of the invention or the mixture of the invention as defined above is readily available on a synthetic basis, even on a commercial scale, and is compatible with the necessary pharmaceuticals or drugs. Has physical quality.

Reaction products of the invention obtained by the process of the invention or as defined above, respectively, and/or oxobutanol esters of polymeric carboxylic acids, in particular polymers as defined above. 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of carboxylic acid, and/or , the mixture obtained by the production process of the invention or the mixture of the invention as defined above can optionally be provided in enantiomerically pure or enantiomerically enriched form.

Reaction products of the invention obtained by the process of the invention or as defined above, respectively, and/or oxobutanol esters of polymeric carboxylic acids, in particular polymers as defined above. 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of carboxylic acid, and/or , the mixture obtained by the production process of the invention or the mixture of the invention as defined above thereby represents an efficient pharmacological drug target in keto therapy of the human or animal body. It is something.

Below, remaining aspects of the invention are described in more detail.
A further subject of the invention is, according to a third aspect of the invention, a reaction product obtained by the method of the invention or a reaction product of the invention as defined above, and/or a high Oxobutanol esters of molecular carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy) of polymeric carboxylic acids as defined above. _A pharmaceutical composition _, in particular a drug or It is a pharmaceutical product.

In particular, according to this aspect of the invention, the invention provides a pharmaceutical composition for prophylactic and/or therapeutic treatment or in the prophylactic and/or therapeutic treatment of diseases of the human or animal body. PHARMACEUTICAL COMPOSITIONS FOR USE OF. This is especially true for diseases associated with disorders of energy metabolism, especially keto metabolism, such as cerebral infarction, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, rephagia, epilepsy, dementia, Alzheimer's disease, among others. , neurodegenerative diseases such as Parkinson's disease, multiple sclerosis, fat metabolic diseases such as amyotrophic lateral sclerosis, refeeding syndrome, anorexia, epilepsy, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Neurodegenerative diseases such as amyotrophic lateral sclerosis, fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), mitochondrial diseases such as VL-FAOD and mitochondrial thiolase deficiency, Huntington's disease, T-cell lymphoma, and stellate cells. lyosomal storage in cancers such as cancer, glioblastoma, rheumatic diseases such as HIV, rheumatoid arthritis, and urica arthritis, chronic inflammatory bowel diseases, especially gastrointestinal diseases such as ulcerative colitis and Crohn's disease, and glycosphingolipidosis. It concerns the effects and side effects of diseases, particularly Niemann-Pick disease, diabetes, and chemotherapy.

A further subject of the invention is also a disease of the human or animal body, in particular energy metabolism, in particular keto metabolism, for the prophylactic and/or therapeutic treatment of the invention. Diseases associated with disorders of the brain, such as cardiovascular diseases, especially cerebral infarction, stroke, hypoxia, myocardial infarction, rephagia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple Sclerosis, fat metabolic diseases such as amyotrophic lateral sclerosis, refeeding syndrome, anorexia, epilepsy, dementia, neurodegeneration such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. diseases, fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), mitochondrial diseases such as VL-FAOD and mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, Rheumatic diseases such as rheumatoid arthritis and urica arthritis, chronic inflammatory bowel diseases, especially gastrointestinal diseases such as ulcerative colitis and Crohn's disease, lyosomal storage diseases such as glycosphingolipidosis, especially Niemann-Pick disease, diabetes, chemistry Reaction products obtained by the method of the invention or reaction products of the invention as defined above, respectively, for use in the prophylactic and/or therapeutic treatment of therapeutic effects and side effects, and/or , oxobutanol esters of polymeric carboxylic acids, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4- of polymeric carboxylic acids as defined above. (Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters and/or mixtures obtained by the production process of the invention or mixtures of the invention as defined above.

A further subject of the invention is, according to a fifth aspect of the invention, a disease of the human or animal body, in particular a disorder of energy metabolism, in particular keto metabolism, for the prophylactic and/or therapeutic treatment of the invention. Diseases related to, for example, especially cerebral infarction, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, rephagia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis , fat metabolic diseases such as amyotrophic lateral sclerosis, refeeding syndrome, anorexia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), mitochondrial diseases such as VL-FAOD and mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, and rheumatoid arthritis. , rheumatic diseases such as arthritis, chronic inflammatory bowel diseases, especially gastrointestinal diseases such as ulcerative colitis and Crohn's disease, lyosomal storage diseases such as glycosphingolipidosis, especially Niemann-Pick disease, diabetes, and chemotherapy. The reaction product obtained by the method of the invention or the reaction product of the invention as defined above, for the production in the prophylactic and/or therapeutic treatment of effects and side effects, respectively, and/or the reaction product of the invention as defined above. Oxobutanol esters of molecular carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy) of polymeric carboxylic acids as defined above. -C ₃ -C ₅ -alkoxy)-2-butanol esters and/or the use of mixtures obtained by the process of the invention or mixtures of the invention as defined above.

Similarly, a further subject of the invention is, according to the sixth aspect of the invention, for prophylactic and/or therapeutic treatment or for application to catabolic metabolic conditions such as fasting, dieting or low carbohydrate nutrition. a reaction product obtained by the process of the invention or a reaction product of the invention as defined above, and/or an oxobutanol ester of a polymeric carboxylic acid, respectively, for the production of a medicament for 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy) of polymeric carboxylic acids, especially as defined above. )-2-butanol ester and/or the use of a mixture obtained by the process of the invention or a mixture of the invention as defined above.

A further subject of the invention is likewise, according to a seventh aspect of the invention, the reaction products obtained by the method of the invention or as defined above, and/or the reaction products of the invention as defined above, respectively. or oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4 of polymeric carboxylic acids as defined above. -(Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or the mixture obtained by the production process of the invention or the food product and/or comprising the mixture of the invention as defined above It is a food product.

According to a particular embodiment, said food and/or food product is essentially a nutraceutical, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant, or strength and/or endurance sports supplements.

Finally, another subject of the invention is, according to an eighth aspect of the invention, the reaction products obtained by the method of the invention or the invention as defined above in foods and food products, respectively. and/or oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol of polymeric carboxylic acids as defined above. esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters and/or mixtures obtained by the process of the invention or of the invention as defined above. is the use of a mixture,

According to this aspect of the invention, the food and/or food product is in particular a nutraceutical, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant or a muscle and/or an endurance sports supplement.

Further embodiments, modifications and variations of the present invention may be readily recognized or effected by those skilled in the art upon reading the specification without departing from the scope of the present invention.

The present invention is illustrated by the following examples, which are not intended to limit the invention in any way, but are merely illustrative of exemplary and non-limiting implementations and configurations of the invention.

Abbreviations used : 3-BHB-EE=BHB-EE: 3-hydroxybutyric acid ethyl ester (=3-hydroxybutanoate ethyl or 4-ethoxy-4-oxobutan-2-ol) (reactant).
・EE-BHB-PWS: 3-hydroxybutanoic acid ethyl ester of polytartaric acid ・EE-BHB-PAS: 3-hydroxybutanoic acid ethyl ester of polyphosphoric acid ・EE-BHB-PCS: 3-hydroxybutanoic acid ethyl ester of polycitric acid ester

I. Preparation Example of a Particular Embodiment of the Process According to the Invention Without Catalysts
I. 1. Preparation of 4-ethoxy-4-oxobutan-2-ol ester of metatartaric acid (=3-hydroxybutanoic acid ethyl ester) In a 100 mL multi-neck flask equipped with a dephlegmator (partial condenser) and a distillation bridge, 11 g of (R)/(S)-3-hydroxybutanoic acid ethyl ester (3-BHB-EE=ethyl 3-hydroxybutanoate or 4-ethoxy-4-oxobutan-2-ol) (racemic) and 5 g of metatartaric acid ( polytartaric acid) is supplied. The reaction mixture was stirred for 6 hours at 120° C. and the reaction water obtained was continuously removed by distillation. Samples of the reaction mixture for further analysis are taken after 3 and 6 hours. The water of reaction is removed by distillation. The excess 3-hydroxybutanoic acid ethyl ester is then evaporated in a nitrogen stream at 70° C. before another sample is taken. The resulting residue is steamed in high vacuum for 2-4 hours.

Mixtures of ethyl 3-hydroxybutanoate mono-, di- and higher esters of metatartaric acid (i.e. metatartaric acid mono(4-ethoxy-4-oxo-butan-2-ol) ester, metatartaric acid di(4-ethoxy-4 A mixture of -oxo-butan-2-ol) ester and metatartaric acid poly(4-ethoxy-4-oxo-butan-2-ol) ester) is obtained.

Characterization is performed by gel permeation chromatography (GPC) and acid value measurement.

The acid value (SZ) indicates the mass of potassium hydroxide (KOH) required to neutralize 1 g of the acid to be analyzed (here, metatartaric acid) in milligrams (mg). Acid value is an index representing the carboxylic acid group in a compound, and is used to quantify the acidity of a substance.

The acid value of pure metatartaric acid (reactant) is 469 mgKOH/g, and the acid value of the obtained reaction product is 190 mgKOH/g. Thus, since the number of free carboxylic acid groups was significantly reduced, esterification with ethyl 3-hydroxybutyrate was successful.

The samples collected during the synthesis (after 3 hours of reaction time, after 6 hours of reaction time, after nitrogen evaporation) and pure metatartaric acid (reactant) were analyzed by gel permeation chromatography (GPC), and the GC area analysis is shown in Table 2. Summarized in:

＊ 酒石酸 ＊＊ ３－ＢＨＢ－ＥＥ

* Tartaric acid ** 3-BHB-EE

The reaction process is schematically shown as follows:

I. 2. Preparation of 4-ethoxy-4-oxobutan-2-ol ester of polymalic acid (=3-hydroxybutanoic acid ethyl ester) In a 100 mL multi-neck flask equipped with a dephlegmator (partial condenser) and a distillation bridge, 11 g of Provides (R)/(S)-3-hydroxybutanoic acid ethyl ester (3-BHB-EE=3-hydroxybutanoic acid or 4-ethoxy-4-oxobutan-2-ol) (racemic) and 5 g of polymalic acid. do. The reaction mixture is stirred at 120° C. for 6 hours to react, and the resulting reaction water is continuously removed by distillation. The excess 3-hydroxybutyric acid ethyl ester is then evaporated at 70° C. in a stream of nitrogen, after which another sample is taken. The resulting residue is steamed in high vacuum for 2-4 hours.

A mixture of ethyl 3-hydroxybutanoate mono-, di-, and higher esters of polymalic acid is obtained.

Characterization is performed by gel permeation chromatography (GPC) and acid value measurement.

I. 3. Preparation of 4-ethoxy-4-oxobutan-2-ol ester of polycitric acid (=3-hydroxybutanoic acid ethyl ester) In a 100 mL multi-neck flask equipped with a dephlegmator (partial condenser) and distillation bridge, 11 g (R)/(S)-3-hydroxybutyric acid ethyl ester (3-BHB-EE=ethyl 3-hydroxy-butanoate or 4-ethoxy-4-oxobutan-2-ol) (racemic form), and 5 g polycitric acid I will provide a. The reaction mixture is stirred at 120° C. for 6 hours to react, and the resulting reaction water is continuously removed by distillation. The excess 3-hydroxybutanoic acid ethyl ester is then evaporated at 70° C. in a nitrogen stream before another sample is taken. The resulting residue is steamed in high vacuum for 2-4 hours.

A mixture of ethyl 3-hydroxybutanoate mono-, di- and higher esters of polycitric acid is obtained.

Characterization is performed by gel permeation chromatography (GPC) and acid value measurement.

I. 4. Further production of 4-ethoxy-4-oxobutan-2-ol ester (=3-hydroxybutanoic acid ethyl ester) of polymeric carboxylic acid Furthermore, the above Synthesis No. I. 1.I. 2.I. 3 are repeated in each case, but each with a different 3-hydroxybutanoic acid ester (i.e. in each case instead of 3-hydroxybutanoic acid ethyl ester 3-hydroxybutanoic acid (hydroxybutyl) ester or 3-hydroxybutanoic acid ( Hydroxypentyl)) is used. 3-Hydroxybutyric acid (hydroxybutyl) ester is obtained by esterifying 3-hydroxybutyric acid with butanediol (e.g. 1,3 butanediol), and 3-hydroxybutyric acid (hydroxypentyl) ester is obtained by esterifying 3-hydroxybutyric acid with butanediol (e.g. 1,3 butanediol). Obtained by esterification of pentanediol (eg 1,3 pentanediol). Equivalent results are obtained. Purification and separation are also carried out in the same manner.

The preparation examples described above are also repeated, but using methyl and ethyl esters of polymeric carboxylic acids. Similar results are obtained. Purification and separation are also carried out in the same manner.

II. Preparation example of an alternative specific embodiment of the method according to the invention using a metal catalyst
All the chemical synthesis examples described above in Section I above are carried out again, but with the addition of titanium tetrabutylate as catalyst (titanium(IV)-catalyst). Titanium(IV)-catalyst is provided in a flask along with other reactants. The reaction method then corresponds to the previous example. Equivalent results are obtained. The catalyst is separated at the end of the reaction and recycled.

III. Preparation example of a further alternative specific embodiment of the method according to the invention using enzyme catalysis
All of the chemical synthesis examples described above in Section I above were performed with the exception that immobilized enzymes (Candida antartica, such as Novozym® 435, commercially available from Sigma-Aldrich or Merck, or Lipozym, commercially available from Ström Chemical) were used as catalysts. CALB lipase on a polymeric support derived from ® 435) is added and carried out at 70° C. under vacuum. Equivalent results are obtained. After the reaction is complete, the catalyst (=enzyme) is separated and recycled.

IV. Physiological application test: artificial digestion test
Digestion experiment (splitting or cleavage experiment) of 3-hydroxybutanoic acid ester of the present invention of polymeric carboxylic acid
Cleavage experiments have shown that the 3-hydroxybutanoic acid esters of polymeric carboxylic acids or mixtures thereof prepared according to the invention, including reaction by-products (see previously described experiments according to Sections I, II and III above), are It has been shown that it can be cleaved in the human gastrointestinal tract.

In each case, the purified reaction products obtained by the process of the invention (i.e. 3-hydroxybutanoic esters of polytartaric acid, 3-hydroxybutanoic esters of polyphosphoric acid and 3-hydroxybutanoic esters of polycitric acid) is used as the starting mixture.

Two media were considered for cleavage experiments under nearbody conditions.
・FaSSGF that simulates the stomach
・FaSSIF that simulates the intestinal tract
Both media are manufactured by Biorelevant (registered trademark), UK. Porcine pancreas (Panzytrat® 40,000, manufactured by Fa. Allergan) was also added in some experiments.

The results of cleavage experiments in FaSSGF or FaSSIF medium in the presence and absence of Panzytrat® (both at 35°C for 24 hours) show that under FaSSGF conditions with and without Panzytrat®, the samples are hydrolyzed. This is mainly due to the low pH value of the medium (pH=1.6). Under FaSSIF conditions, a low conversion using Panzytrat® is performed.

Cleavage experiments show that the cleavage of 3-hydroxybutanoic acid proceeds in a cascade (i.e., 3-hydroxybutanoic acid is released stepwise, followed by further cleavage to free 3-hydroxybutanoic acid and ethanol). ).

V. Further digestion experiments (cleavage experiments) of the inventive carboxylic acids of 3-hydroxybutanoic acid esters
Cleavage experiment using pancreatin
2 g of 3-hydroxybutanoic acid ester of a polymeric carboxylic acid prepared as described above or the corresponding mixture is dissolved in 50 g of water and 0.5 g (1% by weight) of pancreatin is added. Pancreatin is used in the form of Panzytrat® 40,000, commercially available from Allergan. The entire mixture is stirred on a hot plate at 50° C. and the progress of the reaction is measured and monitored by continuously recording the acid number over time. During the observation period, the acid value increases (3-hydroxybutanoic acid ester of the polymeric carboxylic acid cleaves to free 3-hydroxybutanoic acid). Conversion of aqueous cleavage of 3-hydroxybutanoic acid esters of polymeric carboxylic acids according to the invention by pancreatin - time course includes an increase in acid number over time, and the free polymeric carboxylic acids and 3-hydroxy of the reactant mixture Demonstrates the desired decomposition to butanoic acid. This can also be confirmed from the corresponding analysis results. This experiment demonstrates that the starting mixture according to the invention is a suitable physiological precursor of 3-hydroxybutanoic acid or its ester (3-hydroxybutanoic acid ester) for the corresponding ketotherapy. be.

Experiments are carried out and verified in each case using the individual esters in pure form. Similar results are obtained in each case. That is, the 3-hydroxybutanoic acid ester of the polymeric carboxylic acid is each cleaved by pancreatin to give a free polymeric carboxylic acid and a 3-hydroxybutanoic acid ester.

The above cleavage experiments demonstrate that the free hydroxybutanoic acid or ester thereof (herein This shows that it is an efficient precursor or metabolite of ethyl ester, hydroxybutyl ester, hydroxypentyl ester). Similarly, metabolically usable or convertible polymeric carboxylic acids based on carboxylic acids occurring in natural metabolism (e.g. the citric acid cycle) are also formed (e.g. polycitric acid or polycitrates, polyphosphoric acid or polyphosphates). salts, polytartaric acid or metatartaric acid or polytartrates, etc.).

VI. Further testing (organic food and toxicity testing)
Further experiments and test series are carried out regarding the organic properties and toxicity of 3-hydroxybutanoic acid esters of polymeric carboxylic acids according to the invention. For these reasons, the 3-hydroxybutanoic acid esters of polymeric carboxylic acids of the present invention are organically acceptable and compatible, particularly when compared to pure 3-hydroxybutanoic acid and its salts and esters. It can be seen that it exhibits improved organic properties and does not exhibit toxicity that is inconsistent with the present invention.

Claims (56)

Oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester,
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl The general formula (I) is
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is reacted with the especially polycondensed or polymerized carboxylic acid (II) of at least one polymer having at least 3 carboxy groups, especially during the esterification reaction and /or react under esterification conditions,
This provides, as reaction product (III), one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2- A method characterized in that a butanol ester or a 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester can be obtained. 2. Process according to claim 1, characterized in that the compound of general formula (I) is used in the form of racemate or (R)-enantiomer. In the general formula (I), the radical R ¹ is ethyl, and/or
As the compound of general formula (I), ethyl 3-hydroxybutanoate (3-hydroxybutanoic acid ethyl ester or 4-ethoxy-4) of formula CH ₃ -CH(OH)-CH ₂ C(O)OC ₂ H ₅ 3. Process according to claim 1, characterized in that -oxo-2-butanol) is used. The polymeric carboxylic acid (II) is used in the form of a free carboxylic acid, a (partial) salt of a polymeric carboxylic acid or a (partial) ester of a polymeric carboxylic acid, in particular a free polymeric carboxylic acid (II). Process according to any one of claims 1 to 3, characterized in that it is used in acid form. Process according to any one of claims 1 to 4, characterized in that the polymeric carboxylic acid (II) is produced by polycondensation or by polymerization, in particular by ring-opening polymerization. The method according to any one of claims 1 to 5, characterized in that the polymeric carboxylic acid (II) is an ingredient, particularly an additive, approved by food law. The method according to any one of claims 1 to 6, characterized in that the polymeric carboxylic acid (II) has two terminals and/or a primary carboxy group. The polymeric carboxylic acid (II) has at least two, especially 2 to 20, preferably 2 to 10, more preferably 3 to Contains 7 repeating units;
In particular, each repeating unit contains at least one free carboxy group; and/or
In particular, the monomeric carboxylic acids underlying the repeating units and/or the polymeric carboxylic acids (II) are from the group of hydroxydi- and polycarboxylic acids, preferably tartaric, malic and citric acids and combinations and mixtures thereof. derived and/or selected; and/or derived and/or selected from tartaric acid; and/or
In particular, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid (II) is a naturally occurring carboxylic acid or a derivative thereof produced in human and/or animal metabolism, especially a reaction product, especially a carboxylic acid or a derivative thereof, in particular being a reaction product; and/or
In particular, according to any one of claims 1 to 7, wherein the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid (II) is an ingredient, especially an additive, approved by the Food Law. the method of. The polymeric carboxylic acids (II) are selected from polymeric hydroxydi- and polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polyphosphoric acid and polycitric acid and their (partial) salts and (partial) esters; combinations and mixtures thereof, more preferably selected from the group of polytartaric acid (metartaric acid or E353) and their (partial) salts and (partial) esters and mixtures, even more preferably polytartaric acid (metartaric acid or E353); The method according to any one of claims 1 to 8, characterized in that: said polymeric carboxylic acid (II) is selected from polytartaric acid (metartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, in particular polytartaric acid (metartaric acid or E353); The method according to any one of claims 1 to 9, characterized in that: The polymeric carboxylic acid (II) has the general formula (IIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIa)
to correspond to;
Here, in general formula (IIa),
- X is an organic radical, saturated or unsaturated, linear, having 3 to 10, preferably 3 to 8 carbon atoms and having 1 to 3 carboxy groups and optionally at least one hydroxy group; or a branched organic radical;
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ and Y ² are saturated or unsaturated straight chains having terminal and/or primary carboxy groups and having 3 to 7 carbon atoms and 4 to 8 oxygen atoms, each independently of the other. or a branched organic radical. The polymeric carboxylic acid (II) has the general formula (IIb)
Y ¹ -[O-cH(COOH)-CHZ-C(O)] _n -Y ² (IIb)
to correspond to;
Here, in general formula (IIa),
・Z represents hydrogen or hydroxy group;
- The variable n represents an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents the group HOOC-CH(OH)-CH when Z is a hydroxy group Showing (OH)-C(O)-;
・Y ² represents the group -O-CH(COOH)-CH ₂ -COOH when Z is hydrogen, and represents the group -O-CH(COOH)-CH(OH )-COOH. The polymeric carboxylic acid (II) has the general formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
to correspond to;
Here, in general formula (IIc),
- The variable n represents an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH(OH)-C(O)-;
- The method according to any one of claims 1 to 12, characterized in that Y ² represents a group -O-CH(COOH)-CH(OH)-COOH. The polymeric carboxylic acid (II) has the general formula (IId)

to correspond to;
Here, in the general formula (IId), the variable n is an (integer) number of 2 or more, particularly an integer within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7. The method according to any one of claims 1 to 13, characterized in that it shows: Oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, in particular the method according to any one of claims 1 to 14,
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl General formula (I)
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
selected from polymeric hydroxydi- and -polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polyphosphoric acid and polycitric acid, as well as (partial) salts and (partial) esters thereof and combinations and mixtures thereof , more preferably selected from the group of polytartaric acid (metartaric acid or E353) and their (partial) salts and (partial) esters and combinations and mixtures, even more preferably selected from polytartaric acid (metartaric acid or E353) in particular in an esterification reaction and/or under esterification conditions,
Thereby, one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -C ₅ -) of the polymeric carboxylic acid (II), are used as reaction products. A process characterized in that alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained. Oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, in particular the method according to any one of claims 1 to 15,
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl General formula (I)
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
with at least one carboxylic acid (II) selected from polytartaric acid (metartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, especially polytartaric acid (metartaric acid or E353); reacting in an esterification reaction and/or under esterification conditions;
This provides, as reaction product (III), one or more oxobutanol esters of the polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -) of the polymeric carboxylic acid (II). C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)
-2-Butanol ester is obtained. Oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters, in particular the method according to any one of claims 1 to 16,
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl. General formula (I) shown
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
- The variable n represents an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH(OH)-C(O)-,
・^Y2 represents the group -O-CH(COOH)-CH(OH)-COOH General formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
in an ester reaction and/or in esterification conditions, with at least one carboxylic acid (II) of
Thereby, as reaction product (III), one or more oxobutanol esters of polymeric carboxylic acid (II), in particular one or more 4- A process characterized in that oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained . Oxobutanol esters of polymeric carboxylic acids, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, in particular the method according to any one of claims 1 to 17, comprising:
The radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl. General formula (I) shown
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one oxobutanol, in particular at least one 3-hydroxybutanoic acid ester, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-( Hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol is
- The variable n represents an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7. )

in an ester reaction and/or in esterification conditions, with at least one carboxylic acid (II) of
This provides, as reaction product (III), one or more oxobutanol esters of the polymeric carboxylic acid (IId), in particular one or more 4- A process characterized in that oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained . the reaction is carried out in the absence of a solvent and/or without a solvent; and/or
Said reaction is carried out in the absence and/or without a catalyst, or said reaction is carried out in the presence of a catalyst, in particular enzyme- and/or metal-containing and/or metal-based, acidic or basic Process according to any one of claims 1 to 18, characterized in that it is carried out in the presence of a catalyst, in particular that the catalyst is recycled after the reaction. 20. The method according to claim 1, wherein the reaction is carried out in the absence of a solvent and/or without a solvent; and the reaction is carried out in the absence of a catalyst and/or without a catalyst. Any one of the methods. said reaction is carried out in the absence of a catalyst and/or without a catalyst; and said reaction is carried out in the range of 20°C to 160°C, especially in the range of 50°C to 150°C, preferably 70°C to 140°C. and/or
Said reaction is carried out in the absence of a catalyst and/or without a catalyst, in the range from 0.0001 bar to 10 bar, in particular in the range from 0.001 bar to 5 bar, preferably in the range from 0.01 bar to 2 bar. more preferably at a pressure in the range from 0.05 bar to 1 bar, more preferably at a pressure of about 1 bar; and/or
Claim characterized in that the reaction is carried out in the absence of a catalyst and/or without a catalyst, in the presence of an inert gas, in particular in the presence of helium, argon, nitrogen, preferably in the presence of nitrogen. 20. The method according to any one of 1 to 20. said reaction is carried out in the presence of an enzyme as a catalyst;
In particular, said enzyme is selected from synthetases (ligases), catalases, esterases, lipases and combinations thereof; and/or
In particular, the enzymes include Candida antarctica, Mucor miehei, Thermomyces lanuginosa, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus deremar and obtained from Pseudomonas species and combinations thereof, preferably Candida antarctica, Mucor miehei (Rhisomucor miehei) and Thermomyces lanuginosa; and/or
In particular, the enzyme is used in an immobilized form, particularly in a carrier, preferentially a polymer carrier, preferably a hydrophobic polymeric organic carrier, more preferably a poly(meth)acrylic resin carrier. ; and/or;
In particular, the enzyme is recycled after the reaction; and/or
In particular, the reaction is performed within the range of 10°C to 80°C, especially within the range of 20°C to 80°C, preferably within the range of 25°C to 75°C, more preferably within the range of 45°C to 75°C, even more preferably be carried out at a temperature within the range of 50°C to 70°C; and/or
Said enzyme is present in an amount of from 0.001% to 20% by weight, in particular from 0.01% to 15% by weight, preferably from 0.01% to 15% by weight, based on the total amount of starting compounds (I) and (II). used within the range of 1% to 15% by weight, preferably within the range of 0.5% to 10% by weight; and/or
The reaction is carried out at a pressure within the range of 0.0001 bar to 10 bar, in particular within the range of 0.001 bar to 5 bar, preferably within the range of 0.01 bar to 2 bar, more preferably within the range of 0.05 bar to 1 bar, even more preferably about carried out at a pressure of 0.5 bar and in the presence of an enzyme as catalyst; and/or
20. According to any one of claims 1 to 19, the reaction is carried out in the presence of an enzyme and in the presence of an inert gas, in particular helium, argon or nitrogen, preferably nitrogen. the method of. said reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst;
In particular, the catalysts include (i) basic catalysts, especially alkali or alkaline earth hydroxides and alkali or alkaline earth alcohol salts, such as NaOH, KOH, LiOH, Ca(OH) ₂ , NaOMe, KOMe and Na( OBu-tert.), (ii) acidic catalysts, especially mineral acids, and organic acids, such as sulfuric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids. , especially Lewis acids based on titanium, tin, zinc and aluminum compounds, such as titanium tetrabutyrate, stannic acid, zinc acetate, aluminum trichloride, aluminum triisopropyl, and (iv) heterogeneous catalysts, especially mineral silicon selected from those based on acid esters, germanate esters, carbonate esters and aluminum oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas and combinations thereof; and/or
In particular, Lewis acids based on titanium, tin, zinc, aluminum compounds, titanium tetrabutyrate, stannic acid, zinc acetate, aluminum trichloride, aluminum triisopropyl are used as catalysts; and/or
In particular, said catalyst is recycled after the reaction; and/or
In particular, the reaction is carried out in the presence of a metal-containing and/or metal-based, acidic or basic catalyst at a temperature in the range from 20°C to 160°C, especially in the range from 50°C to 150°C, preferably from 70°C to 140°C. and/or
In particular, the catalyst is preferably present in an amount of from 0.01% to 30% by weight, in particular from 0.05% to 15% by weight, based on the total amount of starting compounds (I) and (II). is used in an amount within the range of 0.1% to 15% by weight, preferably within the range of 0.2% to 10% by weight; and/or
Said reaction is carried out at a temperature within the range from 0.0001 bar to 10 bar, in particular within the range from 0.001 bar to 5 bar, preferably within the range from 0.01 bar to 2 bar, more preferably from 0.05 bar to 1 bar. more preferably at a pressure of about 1 bar, in the presence of a metal-containing and/or metal-based, acidic or basic catalyst; and/or
Process according to any one of claims 1 to 19, in particular, wherein the reaction is carried out in the presence of an inert gas, in particular helium, argon or nitrogen, preferably in the presence of nitrogen. The oxobutanol of the general formula (I) based on the carboxy group of the polymeric carboxylic acid (II) is within the range from an equimolar amount to a molar excess of 200 mol%, particularly from an equimolar amount to a molar excess of 150 mol%. preferably in a molar amount ranging from equimolar amounts to a molar excess of 100 mol%; and/or
The oxobutanol of general formula (I) and the polymeric carboxylic acid (II) are in the range of 10:1, such as 1:1K, particularly in the range of 2:1 to 8:1, preferably 3:1 to 6:1. 24. The process according to claim 1, wherein the molar ratio of oxobutanol of general formula (I)/carboxy groups of polymeric carboxylic acid (II) is within the range of 1. . During the reaction of the oxobutanol of the general formula (I) with the polymeric carboxylic acid (II) in the free acid form, water is simultaneously formed, in particular water is recovered from the reaction, in particular continuously recovered, preferably recovered by continuous, in particular distillative or adsorption removal; and/or
During the reaction of the oxobutanol of general formula (I) with the polymeric carboxylic acid (II) in the form of an ester, 1 mole of the corresponding alcohol is formed for each mole of reacted ester group, in particular when the alcohol is 25. Process according to claim 1, characterized in that the process is recovered from, in particular continuously, particularly preferably by continuous distillation or adsorption removal. The composition of the reaction products, in particular the presence of various oxobutanol esters of polymeric carboxylic acids and their proportions in the case of mixtures, can be determined by the reaction conditions, in particular by the selection of the reaction temperature (conversion temperature) and/or or by selecting the reaction pressure (conversion pressure) and/or by providing no catalyst or by providing a catalyst and by selecting the catalyst with respect to type and/or amount; ) and/or by providing for the removal of optionally formed by-products, in particular water and/or alcohol. The method described in any one of . 27. The method according to claim 1, wherein the reaction product obtained is fractionated after the reaction has taken place, in particular by distillation. 28. Process according to any one of claims 1 to 27, characterized in that unreacted starting compounds (I) and/or (II) are separated from the reaction product and then recycled. that the hydroxy and/or carboxy groups still present in the reaction product after said reaction has taken place are at least partially, preferably completely, functionalized, in particular esterified; and/or
29. According to any one of claims 1 to 28, characterized in that the reaction is followed by a partial, in particular complete functionalization, in particular esterification, of the hydroxy and/or carboxy groups still present. the method of. As reaction product (III) one or more oxobutanol esters of polymeric carboxylic acid (II), in particular one or more 4-oxo-4-(C ₁ -C ₅ -) of polymeric carboxylic acid (II) 30. According to any one of claims 1 to 29, characterized in that an alkoxy)-2-butanol ester or a 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester is obtained. the method of. As reaction product (III) one or more oxobutanol esters of polymeric carboxylic acids (II) as defined in any one of claims 33 to 47, in particular one of polymeric carboxylic acids (II) One or more 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters are obtained. Method according to any one of claims 1 to 30, characterized in that: As reaction product (III) a mixture of at least two, in particular at least three different oxobutanol esters of polymeric carboxylic acids (II) as defined above, in particular one or more of polymeric carboxylic acids (II) 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or a mixture of 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of Method according to any one of claims 1 to 31, characterized in that: Reaction products, in particular (chemical) products or product mixtures, obtained by the process according to any one of claims 1 to 32, oxobutanol esters of polymeric carboxylic acids, in particular 4- Oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, or a plurality of polymeric carboxylic acids Mixtures of oxobutanol esters, especially multiple 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy-C ₃ -C ₅ -) of polymeric carboxylic acids. Mixture of alkoxy)-2-butanols. Oxobutanol esters of polymeric carboxylic acids according to claim 33, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol esters or 4-oxo-4-(hydroxy- C ₃ -C ₅ -alkoxy)-2-butanol ester. At least one carboxy group, especially at least one terminal and/or primary carboxy group of the polymeric carboxylic acid is oxobutanol, especially of the general formula (I)
CH ₃ -CH(OH)-CH ₂ -C(O)OR ¹ (I)
at least one 3-hydroxybutanoic acid, preferably at least one 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C ₃ -C ₅ - esterified with alkoxy)-2-butanol,
Here, in the general formula (I), the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, Oxobutanol ester of polymeric carboxylic acid according to claim 34, characterized in that it represents hydroxybutyl or hydroxypentyl, more preferably ethyl. the polymeric carboxylic acid is produced by polycondensation or by polymerization, especially ring-opening polymerization; and/or
The polymeric carboxylic acid is an ingredient, especially an additive, approved by food law; and/or
The oxobutanol ester of a polymeric carboxylic acid according to claim 34 or 35, characterized in that the polymeric carboxylic acid consists of two terminal and/or primary carboxy groups. The polymeric carboxylic acid has at least 2, particularly 2 to 20, preferably 2 to 10, more preferably 3 to 7 repeating units derived from a monomeric carboxylic acid that is the basis of the polymeric carboxylic acid. including;
In particular, said repeating units each contain at least one free carboxy group; and/or
In particular, the monomeric carboxylic acids underlying the repeating units and/or the polymeric carboxylic acids are derived from and/or selected from hydroxydi- and polycarboxylic acids, preferably tartaric acid, malic acid and citric acid, as well as these. derived from and/or selected from the group of combinations and mixtures, more preferably derived from and/or selected from tartaric acid; and/or
In particular, the monomeric carboxylic acid that forms the base of the polymeric carboxylic acid is a naturally occurring carboxylic acid or its derivative produced in human and/or animal metabolism, especially a reaction product, especially a carboxylic acid or its derivative, especially a reaction product. being a product; and/or
The polymeric carboxylic acid according to any one of claims 34 to 36, wherein the monomeric carboxylic acid that forms the basis of the polymeric carboxylic acid is an ingredient, particularly an additive, approved by the Food Law. Oxobutanol ester of acid. Said polymeric carboxylic acids include polymeric hydroxydi- and polycarboxylic acids, preferably polytartaric acid (metartaric acid or E353), polymalic acid and polycitric acid and their (partial) salts and (partial) esters and their selected from the group consisting of combinations and mixtures, more preferably from polytartaric acid (metartaric acid or E353) and their (partial) salts and (partial) esters and mixtures, even more preferably from polytartaric acid (metartaric acid or E353) to be; and/or
characterized in that said polymeric carboxylic acid is selected from polytartaric acid (metatartaric acid or E353) and its (partial) salts and (partial) esters and mixtures thereof, in particular from polytartaric acid (metatartaric acid or E353) The oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 37. The polymeric carboxylic acid has the general formula (IIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIa)
to correspond to;
Here, in general formula (IIa),
- X is an organic radical, in particular a saturated or unsaturated linear radical containing 3 to 10, preferably 3 to 8 carbon atoms and containing 1 to 3 carboxy groups and optionally at least one hydroxy group; or indicating a branched organic radical;
- the variable n indicates an (integer) number greater than or equal to 2, in particular an integer in the range of 2 to 20, preferably an integer in the range of 2 to 10, more preferably an integer in the range of 3 to 7;
・Y ¹ and Y ² are saturated or unsaturated linear chains having terminal and/or primary carboxy groups and having 3 to 7 carbon atoms and 4 to 8 oxygen atoms, respectively or a branched organic radical, the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 37. The polymeric carboxylic acid has the general formula (IIb)
Y ¹ -[O-CH(COOH)-CHZ-C(O)] _n -Y ² (IIb)
to correspond to;
Here, in general formula (IIb),
・Z represents hydrogen or hydroxy group;
- The variable n represents an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents the group HOOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents the group HOOC-CH(OH)-CH(OH) when Z is a hydroxy group -C(O)-;
・Y ² represents a group -O-CH(COOH)-CH ₂ -COOH when Z is hydrogen, and represents a group -O-CH(COOH)-CH(OH)- when Z is a hydroxy group The oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 39, which exhibits COOH. The polymeric carboxylic acid has the general formula (IIc)
Y ¹ -[O-CH(COOH)-CH(OH)-C(O)] _n -Y ² (IIc)
to correspond to;
Here, in general formula (IIc),
- The variable n represents an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7;
・Y ¹ represents a group HOOC-CH(OH)-CH(OH)-C(O)-;
- The oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 40, characterized in that Y ² represents a group -O-CH(COOH)-CH(OH)-COOH. The polymeric carboxylic acid has the general formula (IId)

to correspond to;
Here, in general formula (IId),
- The variable n is characterized by representing an (integer) number of 2 or more, particularly within the range of 2 to 20, preferably within the range of 2 to 10, more preferably within the range of 3 to 7. Oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 41. The oxobutanol ester has the general formula (IIIa)
Y ¹ -[O-X-C(O)] _n -Y ² (IIIa)
to correspond to;
Here, in general formula (IIIa),
- X is an organic radical, in particular a saturated ^or It denotes an unsaturated, straight-chain or branched organic radical, where the radical R ³ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C( O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably Ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ and Y ² are each independently saturated or ^unsaturated , linear or It represents a branched organic radical, where in the group -COOR ⁴ , the radical R ⁴ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl thing;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above, preferably is a polymeric carboxylic acid, characterized in that (as a further) condition, at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above. oxobutanol ester of polymeric carboxylic acid, 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2 - butanol esters, in particular oxobutanol esters of polymeric carboxylic acids according to any one of claims 34 to 42. Oxobutanol ester is
General formula (IIIb)
Y ¹ -[O-CH(COOR ₃ )-CHZ-C(O)] _n -Y ² (IIIb)
It corresponds to
Here, in general formula (IIIb),
・Z represents hydrogen or hydroxy group;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・Y ¹ represents a group R ⁴ OOC-CH(OH)-CH ₂ -C(O)- when Z is hydrogen, and represents a group R ⁴ OOC-CH(OH) when Z is a hydroxy group -CH(OH)-C(O)-, where the radical R ⁴ represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents , C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, more preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl :
・Y ² represents a group -O-CH(COOR ⁴ )-CH ₂ -COOR ⁴ when Z is hydrogen, and represents a group -O-CH(COOR ⁴ )- when Z is a hydroxy group. CH(OH)-COOR ⁴ , where the radical R ⁴ independently of each other represents hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ represents C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl thing;
provided that at least one, in particular at least two of the radicals R ³ and R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -c(O)OR ¹ as defined above; As a further) condition, the polymeric carboxylic acid oxobutanol is characterized in that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above. ester, 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of polymeric carboxylic acid , in particular an oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 43. The oxobutanol ester has the general formula (IIIc)
Y ¹ -[O-CH(COOR ³ )-CH(OH)-C(O)] _n -Y ² (IIIc)
It corresponds to
Here, in the general formula (IIIc),
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
・Y ¹ represents the group R ⁴ OOC-CH(OH)-CH(OH)-C(O)-, where the radical R ⁴ is hydrogen or the radical -CH(CH ₃ )-CH ₂ -C( O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, more preferably ethyl , hydroxybutyl or hydroxypentyl, more preferably ethyl:
・Y ² represents the group -O-CH(COOR ⁴ )-CH(OH)-COOR ⁴ , where the radical R ⁴ is independently of each other hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , in which the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, especially ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably represents ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above; As a further) condition, the polymeric carboxylic acid oxobutanol is characterized in that at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above. ester, 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester of polymeric carboxylic acid , in particular an oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 44. The oxobutanol ester has the general formula (IIId)

It corresponds to
Here, in the general formula (IIId),
- the variable n indicates an (integer) number of 2 or more, particularly an integer in the range of 2 to 20, preferably in the range of 2 to 10, more preferably in the range of 3 to 7;
・R ³ represents hydrogen or a radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ for each repeating unit, where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy -C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
・R ⁴ represents, independently of each other, hydrogen or the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ , where the radical R ¹ is C ₁ -C ₅ -alkyl or hydroxy-C ₃ -C ₅ -alkyl, in particular ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl;
provided that at least one, especially at least two of the radicals R ³ and R ⁴ exhibit the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above, preferably is a polymeric carboxylic acid, characterized in that (as a further) condition, at least one radical R ⁴ represents the radical -CH(CH ₃ )-CH ₂ -C(O)OR ¹ as defined above. oxobutanol ester of polymeric carboxylic acid, 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2 - butanol esters, in particular oxobutanol esters of polymeric carboxylic acids according to any one of claims 34 to 45. A mixture of at least two, in particular at least three different oxobutanol esters of polymeric carboxylic acids, in particular one or more 4-oxo-4-(C ₁ -C ₅ -alkoxy esters of polymeric carboxylic acids as defined above) )-2-butanol ester or a mixture of 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol esters. The reaction product according to claim 33 and/or the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 46, in particular the 4-oxo-4-(C Pharmaceutical composition comprising a _{1- C5} -alkoxy)-2-butanol ester or a 4-oxo-4-(hydroxy- _C3 - _C5 -alkoxy)-2-butanol ester and/or a mixture according to claim 47. a substance, especially a drug or medicine. for prophylactic and/or therapeutic treatment or diseases of the human or animal body, in particular diseases associated with disturbances of energy metabolism, in particular ketone metabolism, such as in particular cerebral infarction, stroke, hypoxia, myocardial Cardiovascular diseases such as infarction, rephagia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, fat metabolic diseases such as multiple sclerosis and amyotrophic lateral sclerosis, refeeding syndrome, Neurodegenerative diseases such as anorexia, epilepsy, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD , mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, rheumatic diseases such as HIV, rheumatoid arthritis, and urica arthritis, chronic inflammatory bowel diseases, especially ulcerative diseases. Claims for use in the prophylactic and/or therapeutic treatment of gastrointestinal diseases such as colitis and Crohn's disease, lyosomal storage diseases such as glycosphingolipidosis, in particular Niemann-Pick disease, diabetes, the effects and side effects of chemotherapy The pharmaceutical composition according to item 48. for prophylactic and/or therapeutic treatment or diseases of the human or animal body, in particular diseases associated with disturbances of energy metabolism, in particular ketone metabolism, such as in particular cerebral infarction, stroke, hypoxia, myocardial Cardiovascular diseases such as infarction, rephagia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, fat metabolic diseases such as multiple sclerosis and amyotrophic lateral sclerosis, refeeding syndrome, Neurodegenerative diseases such as anorexia, epilepsy, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD , mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, rheumatic diseases such as HIV, rheumatoid arthritis, and urica arthritis, chronic inflammatory bowel diseases, especially ulcerative diseases. Claims for use in the prophylactic and/or therapeutic treatment of gastrointestinal diseases such as colitis and Crohn's disease, lyosomal storage diseases such as glycosphingolipidosis, in particular Niemann-Pick disease, diabetes, the effects and side effects of chemotherapy The reaction product according to claim 33 and/or the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 46, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or the mixture according to claim 47. for prophylactic and/or therapeutic treatment or diseases of the human or animal body, in particular diseases associated with disturbances of energy metabolism, in particular ketone metabolism, such as in particular cerebral infarction, stroke, hypoxia, myocardial Cardiovascular diseases such as infarction, rephagia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, fat metabolic diseases such as multiple sclerosis and amyotrophic lateral sclerosis, refeeding syndrome, Neurodegenerative diseases such as anorexia, epilepsy, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, fat metabolic diseases such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD , mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, rheumatic diseases such as HIV, rheumatoid arthritis, and urica arthritis, chronic inflammatory bowel diseases, especially ulcerative diseases. Claims for use in the prophylactic and/or therapeutic treatment of gastrointestinal diseases such as colitis and Crohn's disease, lyosomal storage diseases such as glycosphingolipidosis, in particular Niemann-Pick disease, diabetes, the effects and side effects of chemotherapy The reaction product according to claim 33 and/or the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 46, especially 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or the mixture according to claim 47. 34. Reaction product according to claim 33 for the manufacture of a medicament for prophylactic and/or therapeutic treatment or for application to catabolic metabolic conditions such as fasting, diet or low carbohydrate nutrition. and/or oxobutanol esters of polymeric carboxylic acids according to any one of claims 34 to 46, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2- of polymeric carboxylic acids. Use of a butanol ester or a 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or a mixture according to claim 47. The reaction product according to claim 33 and/or the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 46, in particular 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester and/or a food product comprising a mixture according to claim 47 / or food products. 54. The food according to claim 53, characterized in that it is a nutritional supplement, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant, or a muscle strength and/or endurance sports supplement. and/or food products. The reaction product according to claim 33 and/or the oxobutanol ester of a polymeric carboxylic acid according to any one of claims 34 to 46, in particular of a polymeric carboxylic acid, in foods and/or food products. 4-oxo-4-(C ₁ -C ₅ -alkoxy)-2-butanol ester or 4-oxo-4-(hydroxy-C ₃ -C ₅ -alkoxy)-2-butanol ester, and/or claims Use of the mixture according to 47. that said food and/or food product is a nutritional supplement, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant, or a strength and/or endurance sports supplement; 56. Use according to claim 55, characterized in that: